U.S. patent application number 14/188582 was filed with the patent office on 2014-09-18 for compositions comprising an opioid and an additional active pharmaceutical ingredient for rapid onset and extended duration of analgesia that may be administered without regard to food.
This patent application is currently assigned to MALLINCKRODT LLC. The applicant listed for this patent is MALLINCKRODT LLC. Invention is credited to Krishna R. Devarakonda, Michael J. Giuliani, Vishal K. Gupta, Ralph A. Heasley, Susan Shelby.
Application Number | 20140275143 14/188582 |
Document ID | / |
Family ID | 50290266 |
Filed Date | 2014-09-18 |
United States Patent
Application |
20140275143 |
Kind Code |
A1 |
Devarakonda; Krishna R. ; et
al. |
September 18, 2014 |
Compositions Comprising An Opioid And An Additional Active
Pharmaceutical Ingredient For Rapid Onset And Extended Duration Of
Analgesia That May Be Administered Without Regard To Food
Abstract
The present disclosure provides pharmaceutical compositions
comprising an opioid and an additional active pharmaceutical
ingredient, wherein the composition exhibits gastric retentive
properties which are achieved by a combination of a physical
property of the composition and release of the opioid, wherein upon
administration to a subject, the composition has at least one
pharmacokinetic parameter that differs by less than about 30% when
the subject is in a fasted state as compared to a fed state. The
present disclosure further provides pharmaceutical composition
comprising oxycodone and acetaminophen that provides a rapid onset
of analgesia, and reduced levels of acetaminophen near the end of
the dosing interval. Also provided are an extended release
pharmaceutical composition comprising oxycodone and acetaminophen
that provides reduced abuse potential.
Inventors: |
Devarakonda; Krishna R.;
(Saint Louis, MO) ; Giuliani; Michael J.; (Creve
Coeur, MO) ; Gupta; Vishal K.; (Hillsborough, NJ)
; Heasley; Ralph A.; (Webster Groves, MO) ;
Shelby; Susan; (Town and Country, MO) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MALLINCKRODT LLC |
Hazelwood |
MO |
US |
|
|
Assignee: |
MALLINCKRODT LLC
Hazelwood
MO
|
Family ID: |
50290266 |
Appl. No.: |
14/188582 |
Filed: |
February 24, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61794848 |
Mar 15, 2013 |
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61798525 |
Mar 15, 2013 |
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61871956 |
Aug 30, 2013 |
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61871690 |
Aug 29, 2013 |
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61926027 |
Jan 10, 2014 |
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61928509 |
Jan 17, 2014 |
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Current U.S.
Class: |
514/282 |
Current CPC
Class: |
A61P 43/00 20180101;
A61K 31/167 20130101; A61K 9/209 20130101; A61K 9/2031 20130101;
A61K 31/485 20130101; A61P 29/00 20180101; A61K 31/485 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61P 25/04 20180101;
A61K 31/167 20130101 |
Class at
Publication: |
514/282 |
International
Class: |
A61K 31/485 20060101
A61K031/485; A61K 9/24 20060101 A61K009/24; A61K 9/20 20060101
A61K009/20; A61K 31/167 20060101 A61K031/167 |
Claims
1. A solid oral dosage form comprising: (a) at least one immediate
release portion comprising acetaminophen and oxycodone or a
pharmaceutically acceptable salt thereof; and (b) at least one
extended release portion comprising acetaminophen, oxycodone or a
pharmaceutically acceptable salt thereof, and an extended release
component; wherein the total amount of acetaminophen in the dosage
form is about 325 mg to about 650 mg, and the total amount of
oxycodone or its pharmaceutically acceptable salt in the dosage
form is about 5 mg to about 15 mg; and wherein upon oral
administration of the dosage form to a subject, the dosage form
provides a higher AUC for oxycodone when the dosage form is
administered to the subject in an intact state versus when the
dosage form is administered to the subject in a crushed or ground
state.
2. The solid oral dosage form of claim 1, wherein the extended
release component is an extended release polymer.
3. The solid oral dosage form of claim 2, wherein the extended
release portion comprises, by weight of the extended release
portion, from about 30% to about 50% of the extended release
polymer.
4. The solid oral dosage form of claim 2, wherein the extended
release polymer is polyethylene oxide.
5. The solid oral dosage form of claim 4, wherein the polyethylene
oxide has a molecular weight of about 900,000 Daltons to about
7,000,000 Daltons.
6. The solid oral dosage form of claim 1, wherein upon oral
administration of the dosage form to a subject, the dosage form
provides a longer T.sub.max for oxycodone when the dosage form is
administered to the subject in a crushed or ground state versus
when the dosage form is administered to the subject in an intact
state.
7. The solid oral dosage form of claim 6, wherein administration of
the dosage form to a subject produces a mean T.sub.max for
oxycodone that is at least about 30 minutes greater when the dosage
form is administered in a crushed or ground state versus when the
dosage form is administered in an intact state.
8. The solid oral dosage form of claim 6, wherein administration of
the dosage form to a subject produces a mean T.sub.max for
oxycodone that is at least about 45 minutes greater when the dosage
form is administered in a crushed or ground state versus when the
dosage form is administered in an intact state.
9. The solid oral dosage form of claim 6, wherein administration of
the dosage form to a subject produces a mean T.sub.max for
oxycodone that is at least about 60 minutes greater when the dosage
form is administered in a crushed or ground state versus when the
dosage form is administered in an intact state.
10. The solid oral dosage form of claim 6, wherein administration
of the dosage form to a subject produces a mean T.sub.max for
oxycodone that is at least about 75 minutes greater when the dosage
form is administered in a crushed or ground state versus when the
dosage form is administered in an intact state.
11. The solid oral dosage form of claim 6, wherein administration
of the dosage form to a subject produces a mean T.sub.max for
oxycodone that is at least about 90 minutes greater when the dosage
form is administered in a crushed or ground state versus when the
dosage form is administered in an intact state.
12. The solid oral dosage form of claim 6, wherein administration
of the dosage form to a subject produces a mean T.sub.max for
oxycodone that is at least about 105 minutes greater when the
dosage form is administered in a crushed or ground state versus
when the dosage form is administered in an intact state.
13. The solid oral dosage form of claim 6, wherein administration
of the dosage form to a subject produces a mean T.sub.max for
oxycodone that is at least about 120 minutes greater when the
dosage form is administered in a crushed or ground state versus
when the dosage form is administered in an intact state.
14. The solid oral dosage form of claim 1, wherein upon oral
administration of the dosage form to a subject, the dosage form
provides a AUC(0-1 hr) for oxycodone that is about 50% to about
1000% higher when the dosage form is administered to the subject in
an intact state versus when the dosage form is administered to the
subject in a crushed or ground state.
15. The solid oral dosage form of claim 14, wherein upon oral
administration of the dosage form to a subject, the dosage form
provides a AUC(0-1 hr) for oxycodone that is about 100% to about
900% higher when the dosage form is administered to the subject in
an intact state versus when the dosage form is administered to the
subject in a crushed or ground state.
16. The solid oral dosage form of claim 14, wherein upon oral
administration of the dosage form to a subject, the dosage form
provides a AUC(0-1 hr) for oxycodone that is about 200% to about
800% higher when the dosage form is administered to the subject in
an intact state versus when the dosage form is administered to the
subject in a crushed or ground state.
17. The solid oral dosage form of claim 14, wherein upon oral
administration of the dosage form to a subject, the dosage form
provides a AUC(0-1 hr) for oxycodone that is about 300% to about
700% higher when the dosage form is administered to the subject in
an intact state versus when the dosage form is administered to the
subject in a crushed or ground state.
18. The solid oral dosage form of claim 1, wherein upon oral
administration of the dosage form to a subject, the dosage form
provides a AUC(0-2 hr) for oxycodone that is about 50% to about
500% higher when the dosage form is administered to the subject in
an intact state versus when the dosage form is administered to the
subject in a crushed or ground state.
19. The solid oral dosage form of claim 18, wherein upon oral
administration of the dosage form to a subject, the dosage form
provides a AUC(0-2 hr) for oxycodone that is about 100% to about
400% higher when the dosage form is administered to the subject in
an intact state versus when the dosage form is administered to the
subject in a crushed or ground state.
20. The solid oral dosage form of claim 18, wherein upon oral
administration of the dosage form to a subject, the dosage form
provides a AUC(0-2 hr) for oxycodone that is about 150% to about
300% higher when the dosage form is administered to the subject in
an intact state versus when the dosage form is administered to the
subject in a crushed or ground state.
21. The solid oral dosage form of claim 18, wherein upon oral
administration of the dosage form to a subject, the dosage form
provides a AUC(0-2 hr) for oxycodone that is about 50% to about
250% higher when the dosage form is administered to the subject in
an intact state versus when the dosage form is administered to the
subject in a crushed or ground state.
22. The solid dosage form of claim 1, wherein upon oral
administration of the dosage form to a subject, the dosage form
provides a Tmax for oxycodone that decreases by about 5% to about
70% when the dosage form is administered in an intact state versus
when the dosage form is administered in a crushed or ground
state.
23. The solid dosage form of claim 22, wherein the Tmax for
oxycodone is decreased by about 5% to about 50% when the dosage
form is administered in an intact state versus when the dosage form
is administered in a crushed or ground state.
24. The solid dosage form of claim 22, wherein the Tmax for
oxycodone is decreased by about 5% to about 40% when the dosage
form is administered in an intact state versus when the dosage form
is administered in a crushed or ground state.
25. The solid dosage form of claim 22, wherein the Tmax for
oxycodone is decreased by about 5% to about 30% when the dosage
form is administered in an intact state versus when the dosage form
is administered in a crushed or ground state.
26. The solid dosage form of claim 22, wherein the Tmax for
oxycodone is decreased by about 5% to about 20% when the dosage
form is administered in an intact state versus when the dosage form
is administered in a crushed or ground state.
27. The solid dosage form of claim 22, wherein the Tmax for
oxycodone is decreased by about 10% to about 40% when the dosage
form is administered in an intact state versus when the dosage form
is administered in a crushed or ground state.
28. The solid dosage form of claim 22, wherein the Tmax for
oxycodone is decreased by about 20% to about 60% when the dosage
form is administered in an intact state versus when the dosage form
is administered in a crushed or ground state.
29. The solid dosage form of claim 6, wherein the solid dosage form
contains a total of about 325 mg of acetaminophen and about 5 mg of
oxycodone or its pharmaceutically acceptable salt.
30. The solid dosage form of claim 6, wherein the solid dosage form
contains a total of about 325 mg of acetaminophen and about 7.5 mg
of oxycodone or its pharmaceutically acceptable salt.
31. The solid dosage form of claim 6, wherein the solid dosage form
contains a total of about 325 mg of acetaminophen and about 10 mg
of oxycodone or its pharmaceutically acceptable salt.
32. The solid dosage form of claim 6, wherein the solid dosage form
contains a total of about 325 mg of acetaminophen and about 15 mg
of oxycodone or its pharmaceutically acceptable salt.
33. The solid dosage form of claim 14, wherein the solid dosage
form contains a total of about 325 mg of acetaminophen and about 5
mg of oxycodone or its pharmaceutically acceptable salt.
34. The solid dosage form of claim 14, wherein the solid dosage
form contains a total of about 325 mg of acetaminophen and about
7.5 mg of oxycodone or its pharmaceutically acceptable salt.
35. The solid dosage form of claim 14, wherein the solid dosage
form contains a total of about 325 mg of acetaminophen and about 10
mg of oxycodone or its pharmaceutically acceptable salt.
36. The solid dosage form of claim 14, wherein the solid dosage
form contains a total of about 325 mg of acetaminophen and about 15
mg of oxycodone or its pharmaceutically acceptable salt.
37. The solid dosage form of claim 18, wherein the solid dosage
form contains a total of about 325 mg of acetaminophen and about 5
mg of oxycodone or its pharmaceutically acceptable salt.
38. The solid dosage form of claim 18, wherein the solid dosage
form contains a total of about 325 mg of acetaminophen and about
7.5 mg of oxycodone or its pharmaceutically acceptable salt.
39. The solid dosage form of claim 18, wherein the solid dosage
form contains a total of about 325 mg of acetaminophen and about 10
mg of oxycodone or its pharmaceutically acceptable salt.
40. The solid dosage form of claim 18, wherein the solid dosage
form contains a total of about 325 mg of acetaminophen and about 15
mg of oxycodone or its pharmaceutically acceptable salt.
41. The solid oral dosage form of claim 1, wherein upon oral
administration of the dosage form to a subject, the dosage form
provides a longer T.sub.max for acetaminophen when the dosage form
is administered to the subject in a crushed or ground state versus
when the dosage form is administered to the subject in an intact
state.
42. The solid oral dosage form of claim 41, wherein administration
of the dosage form to a subject produces a mean T.sub.max for
acetaminophen that is at least about one hour greater when the
dosage form is administered in a crushed or ground state as
compared to an intact state.
43. The solid oral dosage form of claim 1, wherein upon oral
administration of the dosage form to a subject, the dosage form
provides a higher C.sub.max for acetaminophen when the dosage form
is administered to the subject in an intact state versus when the
dosage form is administered to the subject in a crushed or ground
state.
44. The solid oral dosage form of claim 1, wherein the total amount
of acetaminophen in the composition is about 325 mg and the total
amount of oxycodone or its pharmaceutically acceptable salt in the
dosage form is about 7.5 mg.
45. The solid oral dosage form of claim 1, wherein the total amount
of acetaminophen in the dosage form is about 325 mg and the total
amount of oxycodone or its pharmaceutically acceptable salt in the
dosage form is about 5 mg.
46. The solid oral dosage form of claim 1, wherein the total amount
of acetaminophen in the dosage form is about 325 mg and the total
amount of oxycodone or its pharmaceutically acceptable salt in the
dosage form is about 10 mg.
47. The solid oral dosage form of claim 1, wherein the total amount
of acetaminophen in the dosage form is about 325 mg and the total
amount of oxycodone or its pharmaceutically acceptable salt in the
dosage form is about 15 mg.
48. A solid oral dosage form comprising: (a) at least one immediate
release portion comprising acetaminophen and oxycodone or a
pharmaceutically acceptable salt thereof; and (b) at least one
extended release portion comprising acetaminophen, oxycodone or a
pharmaceutically acceptable salt thereof, and an extended release
component; wherein the total amount of acetaminophen in the dosage
form is about 325 mg to about 650 mg, and the total amount of
oxycodone or its pharmaceutically acceptable salt in the dosage
form is about 5 mg to about 15 mg; and wherein upon oral
administration of the dosage form to a subject, the dosage form
provides an abuse quotient for oxycodone that is higher when the
dosage form is administered to the subject in an intact state
versus when the dosage form is administered to the subject in a
crushed or ground state.
49. The solid oral dosage form of claim 48, wherein the abuse
quotient for oxycodone is decreased by about 5% to about 90% when
the dosage form is administered in a crushed or ground state versus
when the dosage form is administered in an intact state.
50. The solid oral dosage form of claim 49, wherein the abuse
quotient for oxycodone is decreased by about 10% to about 80% when
the dosage form is administered in a crushed or ground state versus
when the dosage form is administered in an intact state.
51. The solid oral dosage form of claim 49, wherein the abuse
quotient for oxycodone is decreased by about 15% to about 70% when
the dosage form is administered in a crushed or ground state versus
when the dosage form is administered in an intact state.
52. The solid oral dosage form of claim 49, wherein the abuse
quotient for oxycodone is decreased by about 20% to about 60% when
the dosage form is administered in a crushed or ground state versus
when the dosage form is administered in an intact state.
53. The solid oral dosage form of claim 48, wherein the solid
dosage form contains a total of about 325 mg of acetaminophen and
about 5 mg of oxycodone or its pharmaceutically acceptable
salt.
54. The solid oral dosage form of claim 48, wherein the solid
dosage form contains a total of about 325 mg of acetaminophen and
about 7.5 mg of oxycodone or its pharmaceutically acceptable
salt.
55. The solid oral dosage form of claim 48, wherein the solid
dosage form contains a total of about 325 mg of acetaminophen and
about 10 mg of oxycodone or its pharmaceutically acceptable
salt.
56. The solid oral dosage form of claim 48, wherein the solid
dosage form contains a total of about 325 mg of acetaminophen and
about 15 mg of oxycodone or its pharmaceutically acceptable
salt.
57. The solid oral dosage form of claim 48, wherein the extended
release component is an extended release polymer.
58. The solid oral dosage form of claim 57, wherein the extended
release portion comprises, by weight of the extended release
portion, from about 30% to about 50% of the extended release
polymer.
59. The solid oral dosage form of claim 57, wherein the extended
release polymer is polyethylene oxide.
60. The solid oral dosage form of claim 59, wherein the
polyethylene oxide has a molecular weight of about 900,000 Daltons
to about 7,000,000 Daltons.
61. The solid oral dosage form of claim 48, wherein administration
of the dosage form to a subject produces a mean T.sub.max for
oxycodone that is at least about 30 minutes greater when the dosage
form is administered in a crushed or ground state versus when the
dosage form is administered in an intact state.
62. The solid oral dosage form of claim 48, wherein administration
of the dosage form to a subject produces a mean T.sub.max for
oxycodone that is at least about 45 minutes greater when the dosage
form is administered in a crushed or ground state versus when the
dosage form is administered in an intact state.
63. The solid oral dosage form of claim 48, wherein administration
of the dosage form to a subject produces a mean T.sub.max for
oxycodone that is at least about 60 minutes greater when the dosage
form is administered in a crushed or ground state versus when the
dosage form is administered in an intact state.
64. The solid oral dosage form of claim 48, wherein administration
of the dosage form to a subject produces a mean T.sub.max for
oxycodone that is at least about 75 minutes greater when the dosage
form is administered in a crushed or ground state versus when the
dosage form is administered in an intact state.
65. The solid oral dosage form of claim 48, wherein administration
of the dosage form to a subject produces a mean T.sub.max for
oxycodone that is at least about 90 minutes greater when the dosage
form is administered in a crushed or ground state versus when the
dosage form is administered in an intact state.
66. A solid oral dosage form comprising: (a) at least one immediate
release portion comprising acetaminophen and oxycodone or a
pharmaceutically acceptable salt thereof; and (b) at least one
extended release portion comprising acetaminophen, oxycodone or a
pharmaceutically acceptable salt thereof, and an extended release
component; wherein the total amount of acetaminophen in the dosage
form is about 325 mg to about 650 mg, and the total amount of
oxycodone or its pharmaceutically acceptable salt in the dosage
form is about 5 mg to about 15 mg; and wherein administration of
the dosage form to a subject produces a mean T.sub.max for
oxycodone that is at least about 30 minutes greater when the dosage
form is administered in a crushed or ground state versus when the
dosage form is administered in an intact state.
67. The solid oral dosage form of claim 66, wherein administration
of the dosage form to a subject produces a mean T.sub.max for
oxycodone that is at least about 60 minutes greater when the dosage
form is administered in a crushed or ground state versus when the
dosage form is administered in an intact state.
68. The solid oral dosage form of claim 66, wherein administration
of the dosage form to a subject produces a mean T.sub.max for
oxycodone that is at least about 75 minutes greater when the dosage
form is administered in a crushed or ground state versus when the
dosage form is administered in an intact state.
69. The solid oral dosage form of claim 66, wherein administration
of the dosage form to a subject produces a mean T.sub.max for
oxycodone that is at least about 90 minutes greater when the dosage
form is administered in a crushed or ground state versus when the
dosage form is administered in an intact state.
70. The solid oral dosage form of claim 66, wherein the extended
release portion comprises, by weight of the extended release
portion, from about 30% to about 50% of an extended release polymer
comprising polyethylene oxide having a molecular weight of about
900,000 Daltons to about 7,000,000 Daltons.
71. The solid oral dosage form of claim 66, wherein the solid
dosage form contains a total of about 325 mg of acetaminophen and
about 5 mg of oxycodone or its pharmaceutically acceptable
salt.
72. The solid oral dosage form of claim 66, wherein the solid
dosage form contains a total of about 325 mg of acetaminophen and
about 7.5 mg of oxycodone or its pharmaceutically acceptable
salt.
73. The solid oral dosage form of claim 66, wherein the solid
dosage form contains a total of about 325 mg of acetaminophen and
about 10 mg of oxycodone or its pharmaceutically acceptable
salt.
74. The solid oral dosage form of claim 66, wherein the solid
dosage form contains a total of about 325 mg of acetaminophen and
about 15 mg of oxycodone or its pharmaceutically acceptable
salt.
75. The solid oral dosage form of claim 70, wherein upon oral
administration of the dosage form to a subject, the dosage form
provides a AUC(0-1 hr) for oxycodone that is about 50% to about
1000% higher when the dosage form is administered to the subject in
an intact state versus when the dosage form is administered to the
subject in a crushed or ground state.
Description
RELATED CASES
[0001] This application claims priority to U.S. Provisional
Application Nos. 61/794,848 and 61/798,525 filed on Mar. 15, 2013,
U.S. Provisional Application No. 61/871,956 filed on Aug. 30, 2013,
U.S. Provisional Application No. 61/871,690 U.S. filed on Aug. 29,
2013, Provisional Application No. 61/926,027 filed on Jan. 10,
2014, and U.S. Provisional Application No. 61/928,509 filed on Jan.
17, 2014, which are incorporated herein by reference in their
entirety to the full extent permitted by law.
FIELD OF THE INVENTION
[0002] The present disclosure relates to pharmaceutical
compositions comprising an opioid and an additional active
pharmaceutical ingredient wherein the compositions may be
administered under fed or fasted conditions. The present disclosure
further relates to extended release pharmaceutical compositions
comprising oxycodone and acetaminophen that provide a rapid onset
of analgesia, followed by an extended duration of analgesia of
about 12 hours.
BACKGROUND OF THE INVENTION
[0003] Oral drug administration remains the route of choice for the
majority of clinical applications. Modified release (MR) dosage
forms that are administered once or twice daily offer advantages
over their immediate release (IR) counterparts because they reduce
the magnitude of peaks and troughs of drug plasma concentration,
provide longer dosing intervals, sustained analgesic effect, and
increased patient compliance. These modified release formulations
may be referred to as controlled release (CR), sustained release
(SR) and/or extended release (ER) etc. For certain types of
patients, such as those suffering from pain, these MR products may
permit the patient to sleep through the night without having to
wake up during the night to take the next dose. Thus, these dosage
forms can significantly increase the quality of life for such
patients.
[0004] Gastroretentive (GR) dosage formulations have demonstrated
successful delivery of drugs for extended durations of action. One
way to improve drug absorption is to hold a drug delivery system
above the preferred absorption site or window (proximal small
intestine), and maintain the drug release at an appropriate rate.
For example, one strategy is to retain the formulation in the
stomach (gastroretention). Over the last few decades, several
gastroretentive drug delivery approaches have been designed and
developed, including: high density (sinking) systems, which are
retained in the bottom of the stomach, low density systems that
float in gastric fluid due to buoyancy, mucoadhesive systems that
release drugs following bio-adhesion to the gastric mucosa,
superporous hydrogel systems, magnetic systems, and extendible or
swellable systems that expand in the presence of water (gastric
fluid) and fail to pass through the pyloric sphincter of
stomach.
[0005] Parameters controlling the gastric retention of oral dosage
forms include: density, size and shape of the dosage form, food
intake and its nature (particularly fat content), total caloric
content and frequency of intake, posture, gender, age, sex, sleep,
body mass index, physical activity, disease states of the
individual (e.g., diabetes), and administration of drugs with
impact on gastrointestinal transit time, for example, drugs acting
as anticholinergic agents (e.g., atropine, propantheline), opiates
(e.g., codeine) and prokinetic agents (e.g., metoclopramide,
cisapride).
[0006] Food intake (i.e., viscosity of food, food volume, caloric
value, and frequency of feeding) may have a profound effect on the
gastric retention of dosage forms. The presence or absence of food
in the gastrointestinal tract (GIT) influences the gastric
retention time (GRT) of the dosage form. Usually the presence of
food in the gastrointestinal tract (GIT) improves the GRT of the
dosage form and, thus, absorption increases because the drug stays
at the preferred absorption site for a longer period of time.
Indeed, GR formulations of the prior art should be administered
with food in order to achieve the desired bioavailability.
[0007] There is a need, therefore, for extended release GR
compositions comprising an opioid and a second active agent,
wherein bioavailability of such composition is independent of food
intake, thereby increasing the flexibility and ease of the
administration of the composition.
[0008] Researchers have also combined various classes of pain drugs
to provide better analgesia to patients. For example, a combination
of acetaminophen-oxycodone hydrochloride is commercially available
as Percocet and acetaminophen-hydrocodone bitartrate as Vicodin. In
randomized controlled trials, it was shown that the combination
product Percocet was statistically superior to MR oxycodone in
various outcome measures of pain relief. Other combination products
such as Acetaminophen-Hydrocodone and Acetaminophen-Tramadol are
either available or described in the literature. It is postulated
that the combination of two analgesic drugs with complementary
mechanisms of action results in enhanced analgesia due to an
additive effect, an "opioid-sparing" effect, and an improved side
effect and safety profile. The improved safety profile results from
the use of reduced doses of two analgesics with different
side-effects rather than an equieffective dose of a single
agent.
[0009] Acetaminophen is absorbed from the small intestine and
primarily metabolized by conjugation, like glucuronidation and
sulfation, in the liver to nontoxic, water-soluble compounds that
are eliminated in the urine. When the maximum daily dose is
exceeded over a prolonged period, metabolism by conjugation becomes
saturated, and excess acetaminophen is oxidatively metabolized by
cytochrome P450 (CYP) enzymes (e.g., CYP2E1, 1A2, 2A6, 3A4) to a
reactive metabolite, N-acetyl-p-benzoquinone-imine (NAPQI). NAPQI
is a reactive free radical with an extremely short half-life that
is rapidly inactivated by conjugation with glutathione, which is
acting as a sulfhydryl donor. Once the pool of available
glutathione is exhausted, the cysteines of cellular proteins become
sulfhydryl donors to NAPQI, binding covalently and initiating a
cascade of oxidative and cellular damage, resulting in necrosis
and, ultimately, liver failure. Thus, avoiding excessive NAPQI
formation is an important strategy when using acetaminophen,
although to date acetaminophen-sparing has not been an approach any
manufacturers have chosen to take. However, due to the prevalence
of acetaminophen in many over-the-counter products, it is prudent
to consider acetaminophen-sparing precautions when considering
combination therapy lasting more than a few days to avoid an
inadvertent reduction in glutathione stores.
[0010] Thus, various options for pain management are available that
are both IR and MR, and contain either a single drug or a
combination of analgesics. While these combination products provide
the benefits associated with combining two analgesics as described
above, both IR and MR, in itself, have a significant disadvantage.
IR combination products lack the advantages of MR products
described previously. MR combination products lack a significant
benefit associated with IR products--rapid onset of analgesia--that
is extremely desirable for pain management. Because MR products
retard the rate of drug release to sustain the drug effect over
prolonged period, release of drug is slow resulting in significant
time before effective analgesic drug concentration is attained in
the bloodstream. There exists a clinical need for pain management
that combines the desirable features of IR and MR in combination
pain products.
SUMMARY OF THE INVENTION
[0011] Among the various aspects of the present disclosure is
pharmaceutical composition comprising at least one extended release
portion comprising an opioid, an additional active pharmaceutical
ingredient, or a combination thereof, and at least one extended
release component. At least one extended release portion comprises
from about 60% to about 80% of the total amount of the opioid in
the composition, and the composition has gastric retentive
properties that are achieved by a combination of a physical
property of the composition and release of the opioid. Moreover,
when the composition is orally administered to a subject, the
opioid or the additional active pharmaceutical ingredient produces
a plasma profile characterized by at least one pharmacokinetic
parameter that differs by less than about 30% when the subject is
in a fasted state as compared to a fed.
[0012] A further aspect of the disclosure encompasses an extended
release pharmaceutical composition comprising (a) at least one
immediate release portion comprising an opioid, an additional
active pharmaceutical ingredient, or a combination thereof, and (b)
at least one extended release portion comprising an extended
release component and an opioid, an additional active
pharmaceutical ingredient, or a combination thereof. At least one
immediate release portion comprises from about 20% to about 40% of
the total amount of the opioid in the composition, and the
composition has gastric retentive properties that are achieved by a
combination of a physical property of the composition and release
of the opioid. Additionally, when the composition is orally
administered to a subject, the opioid or the additional active
pharmaceutical ingredient in the composition produce a plasma
profile characterized by at least one pharmacokinetic parameter
that differs by less than about 30% when the subject is in a fasted
state as compared to a fed state.
[0013] Still another aspect of the disclosure provides a method for
administering a gastric retentive pharmaceutical composition
comprising an opioid to a subject in need thereof. The method
comprises orally administering an effective amount of the gastric
retentive composition to the subject, the subject being in a fasted
state, wherein the opioid in the composition produces a plasma
profile characterized by at least one pharmacokinetic parameter
that differs by less than about 30% when the subject is in a fasted
state as compared to a fed state.
[0014] Still another aspect of the disclosure provides a method for
administering a gastric retentive pharmaceutical composition
comprising an opioid to a subject in need thereof. The method
comprises orally administering an effective amount of the gastric
retentive composition to the subject, the subject being in a fasted
state, wherein the opioid in the composition produces a plasma
profile characterized by at least one pharmacokinetic parameter
that differs by less than about 30% when the subject is in a fasted
state as compared to a fed state.
[0015] Yet another aspect of the disclosure encompasses a method
for treating pain in a subject in need thereof. The method
comprises orally administering an effective amount of a gastric
retentive pharmaceutical composition comprising an opioid to the
subject in a fasted state, wherein the opioid in the composition
produces a plasma profile characterized by at least one
pharmacokinetic parameter that differs by less than about 30% when
the subject is in a fasted state as compared to a fed state.
[0016] Yet another aspect of the disclosure provides a
pharmaceutical composition for oral administration in the treatment
of pain, comprising (a) at least one immediate release portion
comprising acetaminophen and oxycodone or a pharmaceutically
acceptable salt thereof; and (b) at least one extended release
portion comprising acetaminophen and oxycodone or salt thereof, and
an extended release component, wherein the total amount of
acetaminophen in the composition is about 325 mg to about 650 mg,
and the total amount of oxycodone or salt in the composition is
about 7.5 mg to about 15 mg, and wherein upon placement of the
composition in an in vitro dissolution test comprising USP Paddle
Method at a paddle speed of about 100 rpm in 900 ml of 0.1 N HCl
using a USP type II apparatus at a constant temperature of
37.degree. C., about 30%, by weight, of the oxycodone or salt
thereof is released at about 15 minutes in the test and at least
about 90%, by weight, of the acetaminophen is released at about 8
hours in the test. Further, upon oral administration of a single
dose of the composition to a subject in need of analgesia, the
composition provides a C.sub.max for oxycodone from about 0.9
ng/mL/mg to about 1.6 ng/mL/mg, a C.sub.max for acetaminophen from
about 4.0 ng/mL/mg to about 11.0 ng/mL/mg, a T.sub.max for
oxycodone from about 2 hours to about 7 hours, and a T.sub.max for
acetaminophen from about 0.5 hour to about 6 hours.
[0017] In a further aspect of the disclosure provides a
pharmaceutical composition for oral administration in the treatment
of pain, comprising (a) at least one immediate release portion
comprising acetaminophen and oxycodone or a pharmaceutically
acceptable salt thereof, and (b) at least one extended release
portion comprising acetaminophen and oxycodone or salt thereof, and
an extended release component; wherein the total amount of
acetaminophen in the composition is about 325 mg to about 650 mg,
and the total amount of oxycodone or salt in the composition is
about 7.5 mg to about 15 mg. Moreover, upon placement of the
composition in an in vitro dissolution test comprising USP Paddle
Method at a paddle speed of about 150 rpm in 900 ml of 0.1 N HCl
using a USP type II apparatus at a constant temperature of
37.degree. C., no more than about 65%, by weight, of the total
amount of the oxycodone or salt is released and no more than about
75%, by weight, of the total amount of the acetaminophen is
released after 2 hours; from about 65% to about 85%, by weight, of
the total amount of the oxycodone or salt is released and from
about 70% to about 90%, by weight, of the total amount of the
acetaminophen is released after 4 hours; from about 85% to about
100%, by weight, of the total amount of the oxycodone or salt is
released and from about 85% to about 100%, by weight, of the total
amount of the acetaminophen is released after 8 hours; and from
about 95% to about 100%, by weight, of the total amount of the
oxycodone or salt is released and from about 90% to about 100%, by
weight, of the total amount of the acetaminophen is released after
12 hours.
[0018] An additional aspect of the disclosure provides for a
pharmaceutical composition for oral administration in the treatment
of pain, comprising (a) at least one immediate release portion
comprising acetaminophen and oxycodone or a pharmaceutically
acceptable salt thereof; and (b) at least one extended release
portion comprising acetaminophen and oxycodone or salt thereof, and
an extended release component; wherein the total amount of
acetaminophen in the composition is about 325 mg to about 650 mg,
and the total amount of oxycodone or salt in the composition is
about 7.5 mg to about 15 mg. And upon oral administration of the
composition in an amount of about 15 mg oxycodone or salt and about
650 mg acetaminophen, the composition provides an AUC.sub.0-1.7h
for acetaminophen of about 5.0 ngh/mL/mg to about 13.0 ngh/mL/mg;
an AUC.sub.1.7-48h for acetaminophen of about 25.0 ngh/mL/mg to
about 75.0 ngh/mL/mg; an AUC.sub.0-2.8h for oxycodone or salt of
about 1.0 ngh/mL/mg to about 3.0 ngh/mL/mg; and AUC.sub.2.8-48h of
about 7.5 ngh/mL/mg to about 15.0 ngh/mL/mg.
[0019] Another aspect of the present disclosure is an extended
release pharmaceutical composition comprising at least one extended
release portion comprising oxycodone, acetaminophen, or a
combination thereof, and at least one extended release component.
At least one extended release portion comprises from about 60% to
about 80% of the total amount of the oxycodone in the composition,
and the composition has gastric retentive properties that are
achieved by a combination of a physical property of the composition
and release of the oxycodone. Moreover, when the composition is
orally administered to a subject, the oxycodone or the
acetaminophen produces a plasma profile characterized by at least
one pharmacokinetic parameter that differs by less than about 30%
when the subject is in a fasted state as compared to a fed
state.
[0020] An additional aspect of the present disclosure provides a
dosage form comprising from about 7.5 mg to about 30 mg of
oxycodone and from about 325 mg to about 650 mg of acetaminophen.
The dosage form comprises (a) at least one immediate release
portion comprising about 25% of the total amount of oxycodone in
the composition and about 50% of the total amount of acetaminophen
in the composition; and (b) at least one extended release portion
comprising about 75% of the total amount of oxycodone in the
composition, about 50% of the total amount of acetaminophen in the
composition, and about 35% to about 45%, by weight of the at least
one extended release portion, of an extended release polymer
comprising a polyethylene oxide.
[0021] A further aspect of the disclosure encompasses an extended
release pharmaceutical composition comprising (a) at least one
immediate release portion comprising oxycodone, acetaminophen, or a
combination thereof, and (b) at least one extended release portion
comprising an extended release component and oxycodone,
acetaminophen, or a combination thereof. At least one immediate
release portion comprises from about 20% to about 40% of the total
amount of the oxycodone in the composition, and the composition has
gastric retentive properties that are achieved by a combination of
a physical property of the composition and release of the
oxycodone. Additionally, when the composition is orally
administered to a subject, the oxycodone or the acetaminophen in
the composition produce a plasma profile characterized by at least
one pharmacokinetic parameter that differs by less than about 30%
when the subject is in a fasted state as compared to a fed
state.
[0022] A further aspect of the disclosure provides a method for
reducing the risk of acetaminophen-induced hepatic damage in a
subject being treated for pain with a dosage regimen that comprises
administering to the subject at least two consecutive doses of a
pharmaceutical composition comprising oxycodone and acetaminophen.
The method comprises (a) administering a first dose of the
pharmaceutical composition comprising at least one extended release
portion comprising acetaminophen, oxycodone or a combination
thereof, and an extended release component to the subject, wherein
the composition maintains a therapeutic blood plasma concentration
of oxycodone of at least 5 ng/mL from about 0.75 hours to about 10
hours after administration of the composition, and wherein at least
about 90% of the acetaminophen is released from the composition by
about 8 hours after administration of the composition such that, by
about 10 hours after administration of the composition,
acetaminophen has a blood plasma concentration that is less than
about 30% of acetaminophen's maximum plasma concentration; and (b)
administering a second dose of the pharmaceutical composition to
the subject at about 12 hours after administration of the first
dose.
[0023] Yet another aspect of the disclosure encompasses a method
for treating pain in a subject in need thereof with a
pharmaceutical composition that comprises oxycodone and
acetaminophen. The method comprises orally administering to the
subject an effective amount of pharmaceutical composition
comprising least one extended release portion comprising oxycodone,
acetaminophen or a combination thereof, and an extended release
component, wherein the composition maintains a therapeutic plasma
concentration of oxycodone of at least about 5 ng/mL from about
0.75 hour to about 10 hours after administration of the
composition, and wherein at least about 90% of the acetaminophen is
released from the composition by about 8 hours after administration
of the composition such that, by about 10 hours after
administration of the composition, the blood plasma concentration
of acetaminophen is less than about 30% of acetaminophen's maximum
plasma concentration.
[0024] A further aspect of the disclosure encompasses a
pharmaceutical composition for extended release of oxycodone and
acetaminophen comprising (a) at least one immediate release portion
oxycodone, acetaminophen or a combination thereof, and (b) at least
one extended release portion comprising oxycodone, acetaminophen or
a combination thereof, and an extended release component wherein
about 30% of the oxycodone in the pharmaceutical composition is
released within about 15 minutes of administration and at least
about 90% of the acetaminophen in the pharmaceutical composition is
released in about 8 hours when measured in 900 ml of 0.1N HCl using
a USP type II apparatus at a paddle speed of about 100 rpm and a
constant temperature of 37.degree. C.
[0025] Still another aspect of the disclosure provides a dosage
form comprising (a) an immediate release portion comprising
acetaminophen and oxycodone, wherein the immediate release portion
comprises, by weight of the immediate release portion, from about
70% to about 80% of acetaminophen and from about 0.5% to about 1%
of oxycodone; and (b) an extended release portion comprising
acetaminophen, oxycodone, and an extended release polymer, wherein
the extended release portion comprises, by weight of the extended
release portion, from about 20% to about 40% of acetaminophen, from
about 0.5% to about 2% of oxycodone, and from about 30% to about
50% of the extended release polymer.
[0026] Other features and aspects of the disclosure are described
in detail below.
REFERENCE TO COLOR FIGURES
[0027] This application file contains at least one drawing executed
in color. Copies of this patent application publication with color
drawings will be provided by the Office upon request and payment of
the necessary fee.
BRIEF DESCRIPTION OF THE DRAWINGS
[0028] FIG. 1 presents the in vitro release profile of oxycodone
from oxycodone-acetaminophen bilayer tablets comprising either 15
or 30 mg of oxycodone, 500 mg of acetaminophen (APAP), and either
35% (w/w) POLYOX.RTM. 1105, 45% (w/w) POLYOX.RTM. 1105, or 45%
(w/w) POLYOX.RTM. N60K, as indicated.
[0029] FIG. 2 shows the in vitro release profile of acetaminophen
from oxycodone-acetaminophen bilayer tablets comprising either 15
or 30 mg of oxycodone, 500 mg of acetaminophen (APAP), and either
35% (w/w) POLYOX.RTM. 1105, 45% (w/w) POLYOX.RTM. 1105, or 45%
(w/w) POLYOX.RTM. N60K, as indicated.
[0030] FIG. 3 presents the in vitro release profile of oxycodone
from bilayer tablets comprising 7.5 mg of oxycodone and 325 mg of
acetaminophen, and bilayer tablets comprising 15 mg of oxycodone
and 650 mg of acetaminophen, as indicated.
[0031] FIG. 4 presents the in vitro release profile of
acetaminophen from bilayer tablets comprising 7.5 mg of oxycodone
and 325 mg of acetaminophen, and bilayer tablets comprising 15 mg
of oxycodone and 650 mg of acetaminophen, as indicated.
[0032] FIG. 5 is a graphical representation of the mean plasma
oxycodone concentrations as a function of time after administration
of a single dose of bilayer tablet comprising 15 mg oxycodone/500
mg acetaminophen and having fast, medium, or slow release
properties as compared to an immediate release 7.5 oxycodone/325
acetaminophen tablet administered twice at a 6 hr interval.
[0033] FIG. 6 is a graphical representation of the mean plasma
acetaminophen concentrations as a function of time after
administration of a single dose of bilayer tablet comprising 15 mg
oxycodone/500 mg acetaminophen and having fast, medium, or slow
release properties as compared to an immediate release 7.5
oxycodone/325 acetaminophen tablet administered twice at a 6 hr
interval. The immediate release 7.5 oxycodone/325 acetaminophen
tablet dose was normalized.
[0034] FIG. 7 is a graphical representation of the mean plasma
oxycodone concentrations as a function of time after administration
of a single dose of bilayer tablet comprising 30 mg oxycodone/500
mg acetaminophen and having fast, medium, or slow release
properties as compared to an immediate release 7.5 oxycodone/325
acetaminophen tablet administered twice at a 6 hr interval. The
immediate release 7.5 oxycodone/325 acetaminophen tablet dose was
normalized.
[0035] FIG. 8 is a graphical representation of the mean plasma
acetaminophen concentrations as a function of time after
administration of a single dose of bilayer tablet comprising 30 mg
oxycodone/500 mg acetaminophen and having fast, medium, or slow
release properties as compared to an immediate release 7.5
oxycodone/325 acetaminophen tablet administered twice at a 6 hr
interval. The immediate release 7.5 oxycodone/325 acetaminophen
tablet dose was normalized.
[0036] FIG. 9 shows the mean plasma concentrations of oxycodone
versus time by treatment. Treatment A was one tablet of 15 mg
oxycodone/650 mg acetaminophen administered orally under fed
conditions. Treatment B was two tablets of 15 mg oxycodone/650 mg
acetaminophen administered orally one at a time under fed
conditions. Treatment C was one tablet of an immediate release 7.5
oxycodone/325 acetaminophen tablet administered orally every 6
hours for 2 doses under fed conditions.
[0037] FIG. 10 presents the mean plasma concentrations of
acetaminophen versus time by treatment. Treatment A was one tablet
of 15 mg oxycodone/650 mg acetaminophen administered orally under
fed conditions. Treatment B was two tablets of 15 mg oxycodone/650
mg acetaminophen administered orally one at a time under fed
conditions. Treatment C was one tablet of an immediate release 7.5
oxycodone/325 acetaminophen tablet administered orally every 6
hours for 2 doses under fed conditions.
[0038] FIG. 11 shows the mean plasma concentrations of oxycodone
versus time by treatment. Treatment A was one tablet of 15 mg
oxycodone/650 mg acetaminophen administered orally every 12 hours
for 4.5 days (9 doses) under fed conditions. Treatment B was two
tablets of 15 mg oxycodone/650 mg acetaminophen administered orally
one at a time every 12 hours for 4.5 days (9 doses) under fed
conditions. Treatment C was two tablets of an immediate release 7.5
oxycodone/325 acetaminophen tablet administered orally every 6
hours for 4.5 days (18 doses) under fed conditions.
[0039] FIG. 12 shows the mean plasma concentrations of
acetaminophen versus time by treatment. Treatment A was one tablet
of 15 mg oxycodone/650 mg acetaminophen administered orally every
12 hours for 4.5 days (9 doses) under fed conditions. Treatment B
was two tablets of 15 mg oxycodone/650 mg acetaminophen
administered orally one at a time every 12 hours for 4.5 days (9
doses) under fed conditions. Treatment C was two tablets of an
immediate release 7.5 oxycodone/325 acetaminophen tablet
administered orally every 6 hours for 4.5 days (18 doses) under fed
conditions.
[0040] FIG. 13 presents the mean plasma concentrations of oxycodone
versus time by treatment following oral administration of one
tablet of 15 mg oxycodone/650 mg acetaminophen. Treatment A was
under fed conditions. Treatment B was under fasted conditions.
[0041] FIG. 14 shows the mean plasma concentrations of oxycodone
versus time by treatment following oral administration of two
tablets of 15 mg oxycodone/650 mg acetaminophen. Treatment A was
under fed conditions. Treatment B was under fasted conditions.
[0042] FIG. 15 presents the mean plasma concentrations of
acetaminophen versus time by treatment following oral
administration of one tablet of 15 mg oxycodone/650 mg
acetaminophen. Treatment A was under fed conditions. Treatment B
was under fasted conditions.
[0043] FIG. 16 shows mean plasma concentrations of acetaminophen
versus time by treatment following oral administration of two
tablets of 15 mg oxycodone/650 mg acetaminophen. Treatment A was
under fed conditions. Treatment B was under fasted conditions.
[0044] FIG. 17 illustrates the in vitro release of oxycodone from a
bilayer tablet comprising 7.5 mg of oxycodone/325 mg of
acetaminophen tested in 0.1 N HCl at a paddle speed of 150 rpm
containing 0%, 5%, 20%, or 40% ethanol. Plotted is the percent of
oxycodone released over a period of 2 hours.
[0045] FIG. 18 presents the in vitro release of acetaminophen from
a bilayer tablet comprising 7.5 mg of oxycodone/325 mg of
acetaminophen tested in 0.1 N HCl at a paddle speed of 150 rpm
containing 0%, 5%, 20%, or 40% ethanol. Plotted is the percent of
acetaminophen released over a 2 hour period.
[0046] FIG. 19 shows the mean plasma concentrations of oxycodone as
a function of time by treatment following oral administration of
two tablets of 7.5 mg of oxycodone/325 mg of acetaminophen.
Treatment A was under fed (high fat) conditions. Treatment B was
under fed (low fat) conditions. Treatment C was under fasted
conditions.
[0047] FIG. 20 presents the mean plasma concentrations of
acetaminophen as a function of time by treatment following oral
administration of two tablets of 7.5 mg of oxycodone/325 mg of
acetaminophen. Treatment A was under fed (high fat) conditions.
Treatment B was under fed (low fat) conditions. Treatment C was
under fasted conditions.
[0048] FIG. 21 shows the mean plasma concentrations of oxycodone
versus time by treatment. Treatment A was one tablet of 7.5 mg
oxycodone/325 mg acetaminophen administered orally under fasted
conditions. Treatment B was two tablets of 7.5 mg oxycodone/325 mg
acetaminophen administered orally under fasted conditions.
Treatment C was one tablet of an immediate release 7.5
oxycodone/325 acetaminophen tablet administered orally every 6
hours for 2 doses under fasted conditions. Treatment D was two
tablets of an immediate release 7.5 oxycodone/325 acetaminophen
tablet administered orally every 6 hours for 2 doses under fasted
conditions.
[0049] FIG. 22 presents the mean plasma concentrations of
acetaminophen versus time by treatment. Treatment A was one tablet
of 7.5 mg oxycodone/325 mg acetaminophen administered orally under
fasted conditions. Treatment B was two tablets of 7.5 mg
oxycodone/325 mg acetaminophen administered orally under fasted
conditions. Treatment C was one tablet of an immediate release 7.5
oxycodone/325 acetaminophen tablet administered orally every 6
hours for 2 doses under fasted conditions. Treatment D was two
tablets an immediate release 7.5 oxycodone/325 acetaminophen tablet
administered orally every 6 hours for 2 doses under fasted
conditions.
[0050] FIG. 23 shows a deconvolution plot of the biphasic
absorption of oxycodone from tablets of the 7.5 mg oxycodone/325 mg
acetaminophen formulation. The cumulative amount of oxycodone is
plotted versus time. Circles represent one tablet of 7.5 mg
oxycodone/325 mg acetaminophen; squares represent two tablets of
7.5 mg oxycodone/325 mg acetaminophen; and the immediate release
7.5 oxycodone/325 acetaminophen tablet is shown in a solid line
with no symbols.
[0051] FIG. 24 presents a deconvolution plot of the biphasic
absorption of acetaminophen from tablets of the 7.5 mg
oxycodone/325 mg acetaminophen formulation. The cumulative amount
of acetaminophen is plotted versus time. Circles represent one
tablet of 7.5 mg oxycodone/325 mg acetaminophen; triangles
represent two tablets of 7.5 mg oxycodone/325 mg acetaminophen; and
squares represent the immediate release 7.5 oxycodone/325
acetaminophen product.
[0052] FIG. 25 shows the mean plasma concentrations of oxycodone
versus time by treatment. Treatment A was one tablet of 7.5 mg
oxycodone/325 mg acetaminophen administered orally every 12 hours
for 4.5 days (9 doses) under fasted conditions. Treatment B was two
tablets of 7.5 mg oxycodone/325 mg acetaminophen administered
orally every 12 hours for 4.5 days (9 doses) under fasted
conditions. Treatment C was one tablet of an immediate release 7.5
oxycodone/325 acetaminophen tablet administered orally every 6
hours for 4.5 days (18 doses) under fasted conditions.
[0053] FIG. 26 presents the mean plasma concentrations of
acetaminophen versus time by treatment. Treatment A was one tablet
of 7.5 mg oxycodone/325 mg acetaminophen administered orally every
12 hours for 4.5 days (9 doses) under fasted conditions. Treatment
B was two tablets of 7.5 mg oxycodone/325 mg acetaminophen
administered orally every 12 hours for 4.5 days (9 doses) under
fasted conditions. Treatment C was one tablet of an immediate
release 7.5 oxycodone/325 acetaminophen tablet administered orally
every 6 hours for 4.5 days (18 doses) under fasted conditions.
[0054] FIG. 27A is a bar graph depicting the simulated fractional
absorption of acetaminophen in the upper GIT of a human subject
after treatment of a 7.5 mg oxycodone/325 mg acetaminophen
immediate release formulation.
[0055] FIG. 27B is a bar graph depicting the simulated fractional
absorption of acetaminophen in the upper GIT of a human subject
after treatment of a 7.5 mg oxycodone/325 mg acetaminophen
immediate release formulation, wherein the formulation's transit
time from the stomach through ileum 3 has been doubled.
[0056] FIG. 27C is a bar graph depicting the simulated fractional
absorption of acetaminophen in the upper GIT of a human subject
after treatment of a 7.5 mg oxycodone/325 mg acetaminophen
immediate release formulation, wherein the formulation's transit
time in the stomach has been increased by two hours.
[0057] FIG. 28A is a bar graph depicting the simulated fractional
absorption of oxycodone in the upper GIT of a human subject after
treatment of a 7.5 mg oxycodone/325 mg acetaminophen immediate
release formulation.
[0058] FIG. 28B is a bar graph depicting the simulated fractional
absorption of oxycodone in the upper GIT of a human subject after
treatment of a 7.5 mg oxycodone/325 mg acetaminophen immediate
release formulation, wherein the formulation's transit time from
the stomach through ileum 3 has been doubled.
[0059] FIG. 28C is a bar graph depicting the simulated fractional
absorption of oxycodone in the upper GIT of a human subject after
treatment of a 7.5 mg oxycodone/325 mg acetaminophen immediate
release formulation, wherein the formulation's transit time in the
stomach has been increased by two hours.
[0060] FIG. 29A presents the mean plasma concentrations and Partial
AUCs of acetaminophen (e.g., AUC.sub.0-1.7h and AUC.sub.1.7-48h)
versus time by treatment: (1) Treatment B of Example 10, (2)
Treatment C of Example 9, and (3) Treatment D of Example 10.
[0061] FIG. 29B presents the mean plasma concentrations and Partial
AUCs of oxycodone (e.g., AUC0-2.8 h and AUC2.8-48 h) versus time
treatment: (1) Treatment B of Example 10, (2) Treatment C of
Example 9, and (3) Treatment D of Example 10.
[0062] FIG. 30A presents the mean plasma concentrations and Partial
AUCs of oxycodone versus time for Treatment A of Example 4,
Treatment A of Example 6, and Treatment C of Example 4.
[0063] FIG. 30B presents the mean plasma concentrations and Partial
AUCs of acetaminophen versus time for Treatment A of Example 4,
Treatment A of Example 6, and Treatment C of Example 4.
[0064] FIG. 31 presents oxycodone dissolution data from crushed and
intact immediate release tablets containing 7.5 mg oxycodone and
325 mg acetaminophen.
[0065] FIGS. 32A and 32B present acetaminophen dissolution data
from crushed and intact pharmaceutical formulations described
herein containing a total of 7.5 mg oxycodone and a total of 325 mg
acetaminophen per tablet.
[0066] FIGS. 33A and 33B present oxycodone HCl dissolution data
from crushed and intact pharmaceutical formulations described
herein containing a total of 7.5 mg oxycodone and a total of 325 mg
acetaminophen per tablet.
[0067] FIG. 34 presents acetaminophen dissolution data for three
pharmaceutical formulations described herein. The dissolution data
represents an extended release tablet with the immediate release
data theoretically added. For each formulation, the tablet
contained a total of 9 mg oxycodone HCl and a total of 250 mg
acetaminophen. The three pharmaceutical formulations contained 25%
by weight POLYOX.RTM. 205, 1105, and N-60K, respectively.
[0068] FIG. 35 presents oxycodone HCl dissolution data for the
three pharmaceutical formulations described in FIG. 34.
[0069] FIG. 36 presents acetaminophen dissolution data for three
pharmaceutical formulations described herein. The dissolution data
represents an extended release tablet with the immediate release
data theoretically added. For each formulation, the tablet
contained a total of 9 mg oxycodone HCl and a total of 250 mg
acetaminophen. The three pharmaceutical formulations contained 45%
by weight POLYOX.RTM. 205, 1105, and N-60K, respectively.
[0070] FIG. 37 presents oxycodone HCl dissolution data for the
three pharmaceutical formulations described in FIG. 36.
[0071] FIG. 38 presents acetaminophen dissolution data for four
pharmaceutical formulations described herein. The dissolution data
represents an extended release tablet with the immediate release
data theoretically added. For each formulation, the tablet
contained a total of 9 mg oxycodone HCl and a total of 250 mg
acetaminophen. The four pharmaceutical compositions contained 25%
by weight, 35% by weight, 45% by weight, and 55% by weight
POLYOX.RTM. 1105, respectively.
[0072] FIG. 39 presents oxycodone HCl dissolution data for the
three pharmaceutical formulations described in FIG. 38.
[0073] FIG. 40 presents the in vitro release of oxycodone from a
bilayer tablet comprising 7.5 mg of oxycodone/325 mg of
acetaminophen tested in 0.1 N HCl at a paddle speed of 100 rpm
containing 0%, 5%, 20%, or 40% ethanol. Plotted is the percent of
oxycodone released over a period of 8 hours.
[0074] FIG. 41 presents the in vitro release of acetaminophen from
a bilayer tablet comprising 7.5 mg of oxycodone/325 mg of
acetaminophen tested in 0.1 N HCl at a paddle speed of 100 rpm
containing 0%, 5%, 20%, or 40% ethanol. Plotted is the percent of
acetaminophen released over a 8 hour period.
[0075] FIG. 42 presents the mean plasma concentrations of oxycodone
versus time for A-F of Example 29.
[0076] FIG. 43 presents the mean plasma concentrations of
acetaminophen versus time for Groups A-F of Example 29.
[0077] FIG. 44 presents the mean drug liking scores over time for
Groups A-G of Example 29.
[0078] FIG. 45 presents the mean drug high scores over time for
Groups A-G of Example 29.
[0079] FIG. 46 presents the mean good drug effects scores over time
for Groups A-G of Example 29.
[0080] FIG. 47 presents the baseline adjusted pupillometry scores
versus time for the subjects who completed the study set out in
Example 29.
[0081] FIG. 48 presents the mean plasma concentrations of oxycodone
versus time for Treatments A, B, and D of Example 30.
[0082] FIG. 49 presents the mean plasma concentrations of
acetaminophen versus time for Treatments A, C, and D of Example
30.
[0083] FIG. 50 presents the mean plasma concentrations of oxycodone
versus time for Treatments A, B, and D of Example 31.
[0084] FIG. 51 presents the mean plasma concentrations of
acetaminophen versus time for Treatments A, C, and D of Example
31.
[0085] FIG. 52 presents the plasma oxycodone concentration over
time, as well as half-value duration (HVD) and C.sub.max in a
single dose study in which patients received either a single dose
of immediate-release oxycodone/acetaminophen (two total tablets,
7.5 mg oxycodone/325 mg acetaminophen per tablet administered at 0
h and 6 h) or a single dose of controlled-release
oxycodone/acetaminophen (two total tablets, 7.5 mg oxycodone/325 mg
acetaminophen per tablet, both administered at 0 h).
[0086] FIG. 53 presents the plasma oxycodone concentration over
time, as well as half-value duration (HVD) and mean C.sub.max,
during day 1 of a multi-dose study in which patients received
either immediate-release oxycodone/acetaminophen (7.5 mg
oxycodone/325 mg acetaminophen per tablet administered as one
tablet every 6 hours for 4.5 days) or controlled-release
oxycodone/acetaminophen (two tablets of 7.5 mg oxycodone/325 mg
acetaminophen per tablet (15 mg/650 mg total per dose) administered
every 12 hours for 4.5 days).
[0087] FIG. 54 presents the plasma oxycodone concentration over
time, as well as half-value duration (HVD) and mean C.sub.max,
during steady state (day 5) of a multi-dose study in which patients
received either immediate-release oxycodone/acetaminophen (7.5 mg
oxycodone/325 mg acetaminophen per tablet administered as one
tablet every 6 hours for 4.5 days) or controlled-release
oxycodone/acetaminophen (two tablets of 7.5 mg oxycodone/325 mg
acetaminophen per tablet (15 mg/650 mg total per dose) administered
every 12 hours for 4.5 days).
[0088] FIG. 55 presents the plasma acetaminophen concentration
following single-dose of administration of controlled release
oxycodone/acetaminophen. Patients received either 1 tablet (7.5 mg
oxycodone/325 mg acetaminophen), 2 tablets (15 mg oxycodone/650 mg
acetaminophen), or 4 tablets (30 mg oxycodone/1300 mg
acetaminophen) as a single dose.
[0089] FIG. 56 presents the plasma acetaminophen concentration over
days 1 to 4 during a multi-dose study of controlled-release
oxycodone/acetaminophen. Patients received either 1 tablet (7.5 mg
oxycodone/325 mg acetaminophen) every 12 hours or 2 tablets (15 mg
oxycodone/650 mg acetaminophen) every 12 hours for 4.5 days (9
total doses).
[0090] FIG. 57 presents the steady-state plasma acetaminophen
concentration (hours 96 to 144 on day 5) during a multi-dose study
of controlled-release oxycodone/acetaminophen. Patients received
either 1 tablet (7.5 mg oxycodone/325 mg acetaminophen) every 12
hours or 2 tablets (15 mg oxycodone/650 mg acetaminophen) every 12
hours for 4.5 days (9 total doses).
[0091] FIG. 58 presents the plasma oxycodone concentration
following single-dose of administration of controlled release
oxycodone/acetaminophen. Patients received either 1 tablet (7.5 mg
oxycodone/325 mg acetaminophen), 2 tablets (15 mg oxycodone/650 mg
acetaminophen), or 4 tablets (30 mg oxycodone/1300 mg
acetaminophen) as a single dose.
[0092] FIG. 59 presents the plasma oxycodone concentration over
days 1 to 4 during a multi-dose study of controlled-release
oxycodone/acetaminophen. Patients received either 1 tablet (7.5 mg
oxycodone/325 mg acetaminophen) every 12 hours or 2 tablets (15 mg
oxycodone/650 mg acetaminophen) every 12 hours for 4.5 days (9
total doses).
[0093] FIG. 60 presents the steady-state plasma oxycodone
concentration (hours 96 to 144 on day 5) during a multi-dose study
of controlled-release oxycodone/acetaminophen. Patients received
either 1 tablet (7.5 mg oxycodone/325 mg acetaminophen) every 12
hours or 2 tablets (15 mg oxycodone/650 mg acetaminophen) every 12
hours for 4.5 days (9 total doses).
[0094] FIG. 61 presents the participant-reported visual analog
scale (VAS) scores for drug liking over time for patients receiving
either low-dose intact controlled-release oxycodone/acetaminophen
(2 tablets of 7.5 mg/325 mg, total dose of 15 mg/650 mg) or
low-dose intact immediate-release oxycodone/acetaminophen (2
tablets of 7.5 mg/325 mg, total dose of 15 mg/650 mg).
[0095] FIG. 62 presents the participant-reported visual analog
scale (VAS) scores for drug liking over time for patients receiving
either high-dose intact controlled-release oxycodone/acetaminophen
(4 tablets of 7.5 mg/325 mg, total dose of 30 mg/1300 mg) or
high-dose intact immediate-release oxycodone/acetaminophen (4
tablets of 7.5 mg/325 mg, total dose of 30 mg/1300 mg).
[0096] FIG. 63 presents the participant-reported visual analog
scale (VAS) scores for drug liking over time for patients receiving
either high-dose intact controlled-release oxycodone/acetaminophen
(4 tablets of 7.5 mg/325 mg, total dose of 30 mg/1300 mg) or
high-dose crushed controlled-release oxycodone/acetaminophen (4
tablets of 7.5 mg/325 mg crushed and encapsulated, total dose of 30
mg/1300 mg).
[0097] FIG. 64 presents the participant-reported visual analog
scale (VAS) scores for drug liking over time for patients receiving
either high-dose crushed controlled-release oxycodone/acetaminophen
(4 tablets of 7.5 mg/325 mg crushed and encapsulated, total dose of
30 mg/1300 mg) or high-dose crushed immediate-release
oxycodone/acetaminophen (4 tablets of 7.5 mg/325 mg crushed and
encapsulated, total dose of 30 mg/1300 mg).
[0098] FIG. 65 presents the participant-reported visual analog
scale (VAS) scores for drug high over time for patients receiving
either low-dose intact controlled-release oxycodone/acetaminophen
(2 tablets of 7.5 mg/325 mg, total dose of 15 mg/650 mg) or
low-dose intact immediate-release oxycodone/acetaminophen (2
tablets of 7.5 mg/325 mg, total dose of 15 mg/650 mg).
[0099] FIG. 66 presents the participant-reported visual analog
scale (VAS) scores for drug high over time for patients receiving
either high-dose intact controlled-release oxycodone/acetaminophen
(4 tablets of 7.5 mg/325 mg, total dose of 30 mg/1300 mg) or
high-dose intact immediate-release oxycodone/acetaminophen (4
tablets of 7.5 mg/325 mg, total dose of 30 mg/1300 mg).
[0100] FIG. 67 presents the participant-reported visual analog
scale (VAS) scores for drug high over time for patients receiving
either high-dose intact controlled-release oxycodone/acetaminophen
(4 tablets of 7.5 mg/325 mg, total dose of 30 mg/1300 mg) or
high-dose crushed controlled-release oxycodone/acetaminophen (4
tablets of 7.5 mg/325 mg crushed and encapsulated, total dose of 30
mg/1300 mg).
[0101] FIG. 68 presents the participant-reported visual analog
scale (VAS) scores for drug high over time for patients receiving
either high-dose crushed controlled-release oxycodone/acetaminophen
(4 tablets of 7.5 mg/325 mg crushed and encapsulated, total dose of
30 mg/1300 mg) or high-dose crushed immediate-release
oxycodone/acetaminophen (4 tablets of 7.5 mg/325 mg crushed and
encapsulated, total dose of 30 mg/1300 mg).
[0102] FIG. 69 presents the least-squares mean E.sub.max for drug
liking for patients receiving either high-dose intact
controlled-release oxycodone/acetaminophen (4 tablets of 7.5 mg/325
mg, total dose of 30 mg/1300 mg) or high-dose intact
immediate-release oxycodone/acetaminophen (4 tablets of 7.5 mg/325
mg, total dose of 30 mg/1300 mg).
[0103] FIG. 70 presents the least-squares mean E.sub.max for drug
high and good drug effects for patients receiving either high-dose
intact controlled-release oxycodone/acetaminophen (4 tablets of 7.5
mg/325 mg, total dose of 30 mg/1300 mg) or high-dose intact
immediate-release oxycodone/acetaminophen (4 tablets of 7.5 mg/325
mg, total dose of 30 mg/1300 mg).
[0104] FIG. 71 presents the least-squares mean TE.sub.max for drug
liking, drug high, and good drug effects for patients receiving
either high-dose intact controlled-release oxycodone/acetaminophen
(4 tablets of 7.5 mg/325 mg, total dose of 30 mg/1300 mg) or
high-dose intact immediate-release oxycodone/acetaminophen (4
tablets of 7.5 mg/325 mg, total dose of 30 mg/1300 mg).
[0105] FIG. 72 presents the mean pupillometry scores over time for
patients receiving the following: low-dose intact
controlled-release oxycodone/acetaminophen (2 tablets of 7.5 mg/325
mg, total dose of 15 mg/650 mg); low-dose intact immediate-release
oxycodone/acetaminophen (2 tablets of 7.5 mg/325 mg, total dose of
15 mg/650 mg); high-dose intact controlled-release
oxycodone/acetaminophen (4 tablets of 7.5 mg/325 mg, total dose of
30 mg/1300 mg); high-dose intact immediate-release
oxycodone/acetaminophen (4 tablets of 7.5 mg/325 mg, total dose of
30 mg/1300 mg); high-dose crushed controlled-release
oxycodone/acetaminophen (4 tablets of 7.5 mg/325 mg crushed and
encapsulated, total dose of 30 mg/1300 mg); or high-dose crushed
immediate-release oxycodone/acetaminophen (4 tablets of 7.5 mg/325
mg crushed and encapsulated, total dose of 30 mg/1300 mg).
[0106] FIG. 73 presents simulated oxycodone plasma levels over time
during multidose administration of either controlled-release
oxycodone/acetaminophen or immediate-release
oxycodone/acetaminophen. The solid line represents the simulated
plasma levels for patients receiving two tablets of
controlled-release 7.5 mg oxycodone/325 mg acetaminophen (total
dose of 15 mg/650 mg) every 12 hours for 4.5 days (18 tablets
total). The dashed line represents the simulated plasma levels for
patients receiving one tablet of immediate-release 7.5 mg
oxycodone/325 mg acetaminophen every 6 hours for 4.5 days (18
tablets total).
[0107] FIG. 74 presents the mean steady-state plasma concentration
of oxycodone beginning at the point in time when patients in the
study receiving controlled-release oxycodone/acetaminophen were
administered their last dose. Patients in the study were
administered oxycodone/acetaminophen according to one of the
following three dosing regimens: Treatment A administered 1 tablet
of controlled-release oxycodone/acetaminophen (7.5 mg oxycodone/325
mg acetaminophen) every 12 hours for 4.5 days; Treatment B
administered 2 tablets of controlled-release
oxycodone/acetaminophen (15 mg oxycodone/650 mg acetaminophen total
per dose) every 12 hours for 4.5 days; Treatment C administered 1
tablet of immediate-release oxycodone/acetaminophen (7.5 mg
oxycodone/325 mg acetaminophen) every 6 hours for 4.5 days.
[0108] FIG. 75 presents the mean steady-state plasma concentration
of acetaminophen beginning at the point in time when patients in
the study receiving controlled-release oxycodone/acetaminophen were
administered their last dose. Patients in the study were
administered oxycodone/acetaminophen according to one of the
following three dosing regimens: Treatment A administered 1 tablet
of controlled-release oxycodone/acetaminophen (7.5 mg oxycodone/325
mg acetaminophen) every 12 hours for 4.5 days; Treatment B
administered 2 tablets of controlled-release
oxycodone/acetaminophen (15 mg oxycodone/650 mg acetaminophen total
per dose) every 12 hours for 4.5 days; Treatment C administered 1
tablet of immediate-release oxycodone/acetaminophen (7.5 mg
oxycodone/325 mg acetaminophen) every 6 hours for 4.5 days.
[0109] FIG. 76 presents the mean plasma concentration of oxycodone
over time at steady state for patients completing all study periods
of the study described in Example 37. Patients in the study
received each of the following treatments separately, in one of
four different sequences, with a washout period between them: 2
tablets of controlled-release 7.5 mg oxycodone/325 mg acetaminophen
(15 mg oxycodone/650 mg acetaminophen total per dose) every 12
hours for 4.5 days; 1 tablet of commercially available oxycodone
(15 mg) every 6 hours for 4.5 days; 1 tablet of immediate-release
37.5 mg tramadol/325 mg acetaminophen every 6 hours for 4.5 days;
and 1 tablet of immediate-release 7.5 mg oxycodone/325 mg
acetaminophen every 6 hours for 4.5 days. Only data for the three
treatments with oxycodone are included in FIG. 76.
[0110] FIG. 77 presents the mean plasma concentration of
acetaminophen over time at steady state for patients completing all
study periods of the study described in Example 37. Patients in the
study received each of the following treatments separately, in one
of four different sequences, with a washout period between them: 2
tablets of controlled-release 7.5 mg oxycodone/325 mg acetaminophen
(15 mg oxycodone/650 mg acetaminophen total per dose) every 12
hours for 4.5 days; 1 tablet of commercially available oxycodone
(15 mg) every 6 hours for 4.5 days; 1 tablet of immediate-release
37.5 mg tramadol/325 mg acetaminophen every 6 hours for 4.5 days;
and 1 tablet of immediate-release 7.5 mg oxycodone/325 mg
acetaminophen every 6 hours for 4.5 days. Only data for the three
treatments with acetaminophen are included in FIG. 77.
[0111] FIG. 78 presents the mean plasma concentration of oxycodone
over time for patients completing all study periods of the study
described in Example 38. Patients in the study received each of the
following treatments separately, in one of four different
sequences, with a washout period between them: 2 tablets of
controlled-release 7.5 mg oxycodone/325 mg acetaminophen (15 mg
oxycodone/650 mg acetaminophen total per dose) administered once; 1
tablet of commercially available oxycodone (15 mg) every 6 hours
for two doses; 1 tablet of immediate-release 37.5 mg tramadol/325
mg acetaminophen every 6 hours for two doses; and 1 tablet of
immediate-release 7.5 mg oxycodone/325 mg acetaminophen every 6
hours for two doses. Only data for the three treatments with
oxycodone are included in FIG. 78.
[0112] FIG. 79 presents the mean plasma concentration of
acetaminophen over time for patients completing all study periods
of the study described in Example 38. Patients in the study
received each of the following treatments separately, in one of
four different sequences, with a washout period between them: 2
tablets of controlled-release 7.5 mg oxycodone/325 mg acetaminophen
(15 mg oxycodone/650 mg acetaminophen total per dose) administered
once; 1 tablet of commercially available oxycodone (15 mg) every 6
hours for two doses; 1 tablet of immediate-release 37.5 mg
tramadol/325 mg acetaminophen every 6 hours for two doses; and 1
tablet of immediate-release 7.5 mg oxycodone/325 mg acetaminophen
every 6 hours for two doses. Only data for the three treatments
with acetaminophen are included in FIG. 79.
[0113] FIG. 80 presents the plasma acetaminophen concentration over
time during the first 12 hours after dosing, as well as half-value
duration (HVD) and C.sub.max, in a single dose study in which
patients received either a single dose of immediate-release
oxycodone/acetaminophen (two total tablets, 7.5 mg oxycodone/325 mg
acetaminophen per tablet, 1 tablet administered at 0 h and 1 tablet
at 6 h) or a single dose of controlled-release
oxycodone/acetaminophen (two total tablets, 7.5 mg oxycodone/325 mg
acetaminophen per tablet, both administered at 0 h).
[0114] FIG. 81 presents the plasma acetaminophen concentration over
time during the first 12 hours after initial dosing, as well as
half-value duration (HVD) and C.sub.max, in a multi-dose study in
which patients received either 1 tablet of immediate-release 7.5 mg
oxycodone/325 mg acetaminophen every 6 hours for 4.5 days, or 2
tablets of controlled-release 7.5 mg oxycodone/325 mg acetaminophen
(15 mg/650 mg total per dose) every 12 hours for 4.5 days.
[0115] FIG. 82 presents the steady-state (day 5) plasma
acetaminophen concentration over time, as well as half-value
duration (HVD) and C.sub.max, in a multi-dose study in which
patients received either 1 tablet of immediate-release 7.5 mg
oxycodone/325 mg acetaminophen every 6 hours for 4.5 days, or 2
tablets of controlled-release 7.5 mg oxycodone/325 mg acetaminophen
(15 mg/650 mg total per dose) every 12 hours for 4.5 days.
[0116] FIG. 83 presents the plasma oxycodone concentrations and
patient-reported visual analog scale (VAS) scores for drug liking
over the first 12 hours after dosing in patients receiving either
low-dose intact controlled-release oxycodone/acetaminophen (two
tablets of 7.5 mg oxycodone/325 mg acetaminophen, 15 mg/650 mg
total) or low-dose intact immediate-release oxycodone/acetaminophen
(two tablets of 7.5 mg oxycodone/325 mg acetaminophen, 15 mg/650 mg
total).
[0117] FIG. 84 presents the plasma oxycodone concentrations and
patient-reported visual analog scale (VAS) scores for drug liking
over the first 12 hours after dosing in patients receiving either
high-dose intact controlled-release oxycodone/acetaminophen (four
tablets of 7.5 mg oxycodone/325 mg acetaminophen, 30 mg/1300 mg
total) or high-dose intact immediate-release
oxycodone/acetaminophen (four tablets of 7.5 mg oxycodone/325 mg
acetaminophen, 30 mg/1300 mg total).
[0118] FIG. 85 presents the plasma oxycodone concentrations and
patient-reported visual analog scale (VAS) scores for drug liking
over the first 12 hours after dosing in patients receiving either
high-dose crushed controlled-release oxycodone/acetaminophen (four
tablets of 7.5 mg oxycodone/325 mg acetaminophen, 30 mg/1300 mg
total, crushed and encapsulated) or high-dose crushed
immediate-release oxycodone/acetaminophen (four tablets of 7.5 mg
oxycodone/325 mg acetaminophen, 30 mg/1300 mg total, crushed and
encapsulated).
[0119] FIG. 86 presents the plasma oxycodone concentrations and
patient-reported visual analog scale (VAS) scores for drug high
over the first 12 hours after dosing in patients receiving either
low-dose intact controlled-release oxycodone/acetaminophen (two
tablets of 7.5 mg oxycodone/325 mg acetaminophen, 15 mg/650 mg
total) or low-dose intact immediate-release oxycodone/acetaminophen
(two tablets of 7.5 mg oxycodone/325 mg acetaminophen, 15 mg/650 mg
total).
[0120] FIG. 87 presents the plasma oxycodone concentrations and
patient-reported visual analog scale (VAS) scores for drug high
over the first 12 hours after dosing in patients receiving either
high-dose intact controlled-release oxycodone/acetaminophen (four
tablets of 7.5 mg oxycodone/325 mg acetaminophen, 30 mg/1300 mg
total) or high-dose intact immediate-release
oxycodone/acetaminophen (four tablets of 7.5 mg oxycodone/325 mg
acetaminophen, 30 mg/1300 mg total).
[0121] FIG. 88 presents the plasma oxycodone concentrations and
patient-reported visual analog scale (VAS) scores for drug high
over the first 12 hours after dosing in patients receiving either
high-dose crushed controlled-release oxycodone/acetaminophen (four
tablets of 7.5 mg oxycodone/325 mg acetaminophen, 30 mg/1300 mg
total, crushed and encapsulated) or high-dose crushed
immediate-release oxycodone/acetaminophen (four tablets of 7.5 mg
oxycodone/325 mg acetaminophen, 30 mg/1300 mg total, crushed and
encapsulated).
[0122] FIG. 89 presents a correlation plot for peak drug effects
(E.sub.max) for drug liking versus C.sub.max. The correlation plot
includes data from patients receiving the following forms of
oxycodone/acetaminophen: low-dose intact controlled-release
oxycodone/acetaminophen (two tablets of 7.5 mg oxycodone/325 mg
acetaminophen, 15 mg/650 mg total); low-dose intact
immediate-release oxycodone/acetaminophen (two tablets of 7.5 mg
oxycodone/325 mg acetaminophen, 15 mg/650 mg total); high-dose
intact controlled-release oxycodone/acetaminophen (four tablets of
7.5 mg oxycodone/325 mg acetaminophen, 30 mg/1300 mg total);
high-dose intact immediate-release oxycodone/acetaminophen (four
tablets of 7.5 mg oxycodone/325 mg acetaminophen, 30 mg/1300 mg
total); high-dose crushed controlled-release
oxycodone/acetaminophen (four tablets of 7.5 mg oxycodone/325 mg
acetaminophen, 30 mg/1300 mg total, crushed and encapsulated); or
high-dose crushed immediate-release oxycodone/acetaminophen (four
tablets of 7.5 mg oxycodone/325 mg acetaminophen, 30 mg/1300 mg
total, crushed and encapsulated).
[0123] FIG. 90 presents a correlation plot for peak drug effects
(E.sub.max) for drug high versus C.sub.max. The correlation plot
includes data from patients receiving the following forms of
oxycodone/acetaminophen: low-dose intact controlled-release
oxycodone/acetaminophen (two tablets of 7.5 mg oxycodone/325 mg
acetaminophen, 15 mg/650 mg total); low-dose intact
immediate-release oxycodone/acetaminophen (two tablets of 7.5 mg
oxycodone/325 mg acetaminophen, 15 mg/650 mg total); high-dose
intact controlled-release oxycodone/acetaminophen (four tablets of
7.5 mg oxycodone/325 mg acetaminophen, 30 mg/1300 mg total);
high-dose intact immediate-release oxycodone/acetaminophen (four
tablets of 7.5 mg oxycodone/325 mg acetaminophen, 30 mg/1300 mg
total); high-dose crushed controlled-release
oxycodone/acetaminophen (four tablets of 7.5 mg oxycodone/325 mg
acetaminophen, 30 mg/1300 mg total, crushed and encapsulated); or
high-dose crushed immediate-release oxycodone/acetaminophen (four
tablets of 7.5 mg oxycodone/325 mg acetaminophen, 30 mg/1300 mg
total, crushed and encapsulated).
[0124] FIG. 91 presents a correlation plot for area under the drug
effects curve (AUE) for drug liking versus area under the
concentration-time curve (AUC) for oxycodone. The correlation plot
includes data from patients receiving the following forms of
oxycodone/acetaminophen: low-dose intact controlled-release
oxycodone/acetaminophen (two tablets of 7.5 mg oxycodone/325 mg
acetaminophen, 15 mg/650 mg total); low-dose intact
immediate-release oxycodone/acetaminophen (two tablets of 7.5 mg
oxycodone/325 mg acetaminophen, 15 mg/650 mg total); high-dose
intact controlled-release oxycodone/acetaminophen (four tablets of
7.5 mg oxycodone/325 mg acetaminophen, 30 mg/1300 mg total);
high-dose intact immediate-release oxycodone/acetaminophen (four
tablets of 7.5 mg oxycodone/325 mg acetaminophen, 30 mg/1300 mg
total); high-dose crushed controlled-release
oxycodone/acetaminophen (four tablets of 7.5 mg oxycodone/325 mg
acetaminophen, 30 mg/1300 mg total, crushed and encapsulated); or
high-dose crushed immediate-release oxycodone/acetaminophen (four
tablets of 7.5 mg oxycodone/325 mg acetaminophen, 30 mg/1300 mg
total, crushed and encapsulated).
[0125] FIG. 92 presents a correlation plot for area under the drug
effects curve (AUE) for drug high versus area under the
concentration-time curve (AUC) for oxycodone. The correlation plot
includes data from patients receiving the following forms of
oxycodone/acetaminophen: low-dose intact controlled-release
oxycodone/acetaminophen (two tablets of 7.5 mg oxycodone/325 mg
acetaminophen, 15 mg/650 mg total); low-dose intact
immediate-release oxycodone/acetaminophen (two tablets of 7.5 mg
oxycodone/325 mg acetaminophen, 15 mg/650 mg total); high-dose
intact controlled-release oxycodone/acetaminophen (four tablets of
7.5 mg oxycodone/325 mg acetaminophen, 30 mg/1300 mg total);
high-dose intact immediate-release oxycodone/acetaminophen (four
tablets of 7.5 mg oxycodone/325 mg acetaminophen, 30 mg/1300 mg
total); high-dose crushed controlled-release
oxycodone/acetaminophen (four tablets of 7.5 mg oxycodone/325 mg
acetaminophen, 30 mg/1300 mg total, crushed and encapsulated); or
high-dose crushed immediate-release oxycodone/acetaminophen (four
tablets of 7.5 mg oxycodone/325 mg acetaminophen, 30 mg/1300 mg
total, crushed and encapsulated).
[0126] FIG. 93 presents a summary of the study design for the study
described in Example 12, which was a randomized, double-blind,
placebo-controlled, phase 3 study was conducted to evaluate the
safety and efficacy of controlled-release oxycodone/acetaminophen
in patients with moderate to severe acute pain.
[0127] FIG. 94 presents the mean pain intensity scores during the
first two hours after first metatarsal bunionectomy for patients
receiving either placebo or controlled-release
oxycodone/acetaminophen (two tablets of 7.5 mg oxycodone/325 mg
acetaminophen, total of 15 mg/650 mg per dose) every 12 hours.
[0128] FIG. 95 presents the mean pain intensity scores during hours
0 to 48 after first metatarsal bunionectomy for patients receiving
either placebo or controlled-release oxycodone/acetaminophen (two
tablets of 7.5 mg oxycodone/325 mg acetaminophen, total of 15
mg/650 mg per dose) every 12 hours.
[0129] FIG. 96 presents the proportion of patients with .gtoreq.30%
reduction in pain intensity score at different times during the
first 2 hours of treatment of the study described in Example
12.
[0130] FIG. 97 presents the proportion of patients "satisfied" or
"very satisfied" with placebo or controlled-release
oxycodone/acetaminophen, respectively, according to several
measures of the Global Assessment of Satisfaction as depicted,
after 48 hours of the study described in Example 12, during which
patients received either placebo or two tablets of
controlled-release oxycodone/acetaminophen (total 15 mg
oxycodone/650 mg acetaminophen per dose) every 12 hours after a
first metatarsal bunionectomy.
[0131] FIG. 98 presents the proportion of patients "satisfied" or
"very satisfied" with controlled-release oxycodone/acetaminophen,
according to several measures as depicted, after 7 or 14 days of
open-label phase treatment, during which patients received two
tablets of controlled-release oxycodone/acetaminophen (total 15 mg
oxycodone/650 mg acetaminophen per dose) every 12 hours.
[0132] FIG. 99 presents a summary of the study design for Example
13, which was a multicenter, phase 3, open-label study conducted to
(1) evaluate the safety and tolerability of controlled-release
oxycodone/acetaminophen with up to 35 days of use in patients who
were receiving only nonopioid analgesics but with pain sufficient
to warrant escalation of treatment to opioid therapy and (2)
evaluate the efficacy of controlled-release oxycodone/acetaminophen
using changes from baseline in pain intensity, pain-related quality
of life, and disease-specific quality of life.
[0133] FIG. 100 presents a summary of patient disposition for the
patients participating in the study described in Example 13.
[0134] FIG. 101 presents a summary of the pain intensity score
(brief pain inventory)--both at baseline and at the end of
treatment--for patients receiving two tablets of controlled-release
oxycodone/acetaminophen (total 15 mg oxycodone/650 mg acetaminophen
per dose) every 12 hours for up to 35 days. As summarized in
Example 13, patients participating in the study had either
osteoarthritis of the knee or hip, or chronic low back pain.
[0135] FIG. 102 presents a summary of the Western Ontario and
McMaster Universaties Arthritis Index (WOMAC) domain for
"pain"--both at baseline and at the end of treatment--for patients
with osteoarthritis who received two tablets of controlled-release
oxycodone/acetaminophen (total 15 mg oxycodone/650 mg acetaminophen
per dose) every 12 hours for up to 35 days.
[0136] FIG. 103 presents a summary of the Western Ontario and
McMaster Universaties Arthritis Index (WOMAC) domain for
"stiffness"--both at baseline and at the end of treatment--for
patients with osteoarthritis who received two tablets of
controlled-release oxycodone/acetaminophen (total 15 mg
oxycodone/650 mg acetaminophen per dose) every 12 hours for up to
35 days.
[0137] FIG. 104 presents a summary of the Western Ontario and
McMaster Universaties Arthritis Index (WOMAC) domain for "physical
function"--both at baseline and at the end of treatment--for
patients with osteoarthritis who received two tablets of
controlled-release oxycodone/acetaminophen (total 15 mg
oxycodone/650 mg acetaminophen per dose) every 12 hours for up to
35 days.
[0138] FIG. 105 presents a summary of the Western Ontario and
McMaster Universaties Arthritis Index (WOMAC) total across all
domains--both at baseline and at the end of treatment--for patients
with osteoarthritis who received two tablets of controlled-release
oxycodone/acetaminophen (total 15 mg oxycodone/650 mg acetaminophen
per dose) every 12 hours for up to 35 days.
[0139] FIG. 106 presents stimulated human oxycodone pharmacokinetic
profiles for oxycodone/acetaminophen formulations based on canine
data.
[0140] FIG. 107 presents the pharmacokinetic profiles for oxycodone
and acetaminophen achieved by an embodiment of the present
invention.
DETAILED DESCRIPTION OF THE INVENTION
[0141] Disclosed herein is a combination product of oxycodone and
acetaminophen that has the desirable attributes of both IR and MR
products. The extended release pharmaceutical composition disclosed
herein comprises at least one extended release portion and,
optionally, at least one immediate release portion. The extended
release and immediate release portions may comprise oxycodone,
acetaminophen, or combinations thereof. The at least one immediate
release portion releases acetaminophen (APAP) and/or oxycodone
instantly in an immediate release fashion that provides rapid onset
for the attainment of therapeutically effective plasma
concentrations within about the first 5 minutes, 10 minutes, 15
minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40
minutes, 45 minutes, 50 minutes, 55 minutes, or 60 minutes after
administration of the composition. The at least one extended
release portion releases acetaminophen and/or oxycodone in an
extended release fashion to maintain plasma concentrations above
the minimum effective concentration for about 8-12 hours. In
addition, two other features of this composition are: 1) to allow
the plasma concentrations of oxycodone to fall as rapidly as an
immediate release formulation to provide the same rate of
termination of drug effects as the immediate release product, and
2) to allow the concentrations of APAP to fall even quicker towards
the later part of the dosing interval and bring down the levels of
APAP lower than those of the immediate release product. The
concentrations of APAP in the last quarter of the dosing interval
are comparable to the pre-dose concentrations in a multiple dose
setting, allowing for the glutathione synthase enzyme cycle to
replenish the body's levels of glutathione to avoid the formation
of toxic intermediates with subsequent doses of APAP. Moreover, the
concentrations of APAP in the later part of the dosing interval are
lower than those present when administered a conventional extended
release formulation. This feature has been deliberately introduced
to reduce the hepatic injury due to APAP and is termed "APAP
time-off".
[0142] Abuse potential is a concern with any opioid product. The
addition of APAP to the opioid, however, is likely to reduce the
amount of abuse by illicit routes of administration, particularly
intravenous or intranasal administration. This deterrence is likely
due to the bulk (grams) that the APAP provides as well as the
relative aqueous insolubility compared to freely soluble opioid
salts. Further, APAP is known to be irritating to nasal passages
and to make drug abusers sneeze violently when they are trying to
snort it. In addition, embodiments disclosed herein may be tamper
resistant in that the compositions are difficult to crush for
administration intravenously or intranasally; difficult to extract
with water or alcohol because the mixture becomes too viscous for
injecting or snorting; and resistant to dose dumping in
alcohol.
[0143] In one embodiment, the pharmaceutical composition disclosed
herein, therefore, provides: 1) rapid onset of analgesia within
about 15, 30, 45, or 60 minutes after administration of the
composition mediated by both oxycodone and APAP, with APAP
providing maximal contribution during the early phase; 2) prolonged
analgesia for the entire 12 hours period, mainly contributed by
oxycodone, with minimal fluctuations during this period; 3)
relatively low levels of APAP toward end of dosing interval to
allow for recovery of the depleted hepatic glutathione system; 4)
low abuse quotient; and 5) abuse deterrence.
[0144] In a further embodiment, gastric retentive extended release
pharmaceutical compositions are disclosed comprising at least one
opioid wherein gastric retention of the composition is achieved by
a combination of a physical property of the composition and release
of the opioid. In particular, the opioid is released at a rate that
is sufficient to delay gastric emptying but insufficient to cause
serious adverse gastrointestinal effects. Because gastric retention
of the composition is aided by release of the opioid, oral
administration of the composition is independent of food intake.
That is, the composition may be administered to a subject in either
a fed state or a fasted state. It was discovered that, upon oral
administration to a subject, the composition produces a plasma
profile characterized by at least one pharmacokinetic parameter
that differs by less than about 30% when the subject is in a fasted
state as compared to a fed state. The food independence of this
gastric retentive composition increases the convenience of
administration of the composition in that it may be administered
with or without food. Moreover, this property of the composition
increases patient/subject compliance. The present disclosure also
provides methods for administering the gastric retentive extended
release composition disclosed herein, wherein the composition may
be administered to a subject without regard to meals.
[0145] Headings included herein are simply for ease of reference,
and are not intended to limit the disclosure in any way.
I. DEFINITIONS
[0146] Compounds useful in the compositions and methods include
those described herein in any of their pharmaceutically acceptable
forms, including isomers such as diastereomers and enantiomers,
salts, solvates, and polymorphs, as well as racemic mixtures and
pure isomers of the compounds described herein, where
applicable.
[0147] When introducing elements of the various embodiment(s) of
the present disclosure, the articles "a", "an", "the" and "said"
are intended to mean that there are one or more of the elements.
The terms "comprising", "including" and "having" are intended to be
inclusive and mean that there may be additional elements other than
the listed elements.
[0148] The use of individual numerical values are stated as
approximations as though the values were preceded by the word
"about" or "approximately." Similarly, the numerical values in the
various ranges specified in this application, unless expressly
indicated otherwise, are stated as approximations as though the
minimum and maximum values within the stated ranges were both
preceded by the word "about" or "approximately." In this manner,
variations above and below the stated ranges can be used to achieve
substantially the same results as values within the ranges. As used
herein, the terms "about" and "approximately" when referring to a
numerical value shall have their plain and ordinary meanings to a
person of ordinary skill in the art to which the disclosed subject
matter is most closely related or the art relevant to the range or
element at issue. The amount of broadening from the strict
numerical boundary depends upon many factors. For example, some of
the factors which may be considered include the criticality of the
element and/or the effect a given amount of variation will have on
the performance of the claimed subject matter, as well as other
considerations known to those of skill in the art. As used herein,
the use of differing amounts of significant digits for different
numerical values is not meant to limit how the use of the words
"about" or "approximately" will serve to broaden a particular
numerical value or range. Thus, as a general matter, "about" or
"approximately" broaden the numerical value. Also, the disclosure
of ranges is intended as a continuous range including every value
between the minimum and maximum values plus the broadening of the
range afforded by the use of the term "about" or "approximately."
Consequently, recitation of ranges of values herein are merely
intended to serve as a shorthand method of referring individually
to each separate value falling within the range, unless otherwise
indicated herein, and each separate value is incorporated into the
specification as if it were individually recited herein.
[0149] The term "abuse quotient" for a pharmaceutical composition
as used herein is the numerical value obtained via dividing the
C.sub.max for a drug by the T.sub.max for the same drug. Generally
speaking, the abuse quotient provides a means for predicting the
degree of addictiveness of a given pharmaceutical composition.
Pharmaceutical compositions with lower abuse quotients typically
are less addictive compared to pharmaceutical compositions with
higher abuse quotients.
[0150] The term "active agent" or "drug," as used herein, refers to
any chemical that elicits a biochemical response when administered
to a human or an animal. The drug may act as a substrate or product
of a biochemical reaction, or the drug may interact with a cell
receptor and elicit a physiological response, or the drug may bind
with and block a receptor from eliciting a physiological
response.
[0151] The term "bioequivalent," as used herein, refers to two
compositions, products or methods where the 90% Confidence
Intervals (CI) for AUC, partial AUC and/or Cmax are between 0.80 to
1.25.
[0152] The term "bulk density," as used herein, refers to a
property of powders and is defined as the mass of many particles of
the material divided by the total volume they occupy. The total
volume includes particle volume, inter-particle void volume and
internal pore volume.
[0153] The term "content uniformity," as used herein refers to the
testing of compressed tablets to provide an assessment of how
uniformly the micronized or submicron active ingredient is
dispersed in the powder mixture. Content uniformity is measured by
use of USP Method (General Chapters, Uniformity of Dosage Forms),
unless otherwise indicated. A plurality refers to five, ten or more
tablet compositions.
[0154] The term "friability," as used herein, refers to the ease
with which a tablet will break or fracture. The test for friability
is a standard test known to one skilled in the art. Friability is
measured under standardized conditions by weighing out a certain
number of tablets (generally 20 tablets or less), placing them in a
rotating Plexiglas drum in which they are lifted during replicate
revolutions by a radial lever, and then dropped approximately 8
inches. After replicate revolutions (typically 100 revolutions at
25 rpm), the tablets are reweighed and the percentage of
composition abraded or chipped is calculated.
[0155] The term "ER" as used herein refers to extended release. The
phrases "extended release layer," "ER layer," "ER portion," and
"extended release portion" are used interchangeable in this
document. Further, as used herein the "extended release layer," "ER
layer," "ER portion," and "extended release portion" can be either
(i) a discrete part(s) of the pharmaceutical composition, (ii)
integrated within the pharmaceutical composition, or (iii) a
combination thereof.
[0156] The term "IR" as used herein refers to immediate release.
The phrases "immediate release layer," "IR layer," "IR portion" and
"immediate release portion" are used interchangeable in this
document. In addition, as used herein the "immediate release
layer," "IR layer," "IR portion" and "immediate release portion"
can be either (i) a discrete part(s) of the pharmaceutical
composition, (ii) integrated within the pharmaceutical composition,
or (iii) a combination thereof.
[0157] The term "half life" as used herein refers to the time
required for a drug's blood or plasma concentration to decrease by
one half. This decrease in drug concentration is a reflection of
its metabolism plus excretion or elimination after absorption is
complete and distribution has reached an equilibrium or quasi
equilibrium state. The half life of a drug in the blood may be
determined graphically off of a pharmacokinetic plot of a drug's
blood-concentration time plot, typically after intravenous
administration to a sample population. The half life can also be
determined using mathematical calculations that are well known in
the art. Further, as used herein the term "half life" also includes
the "apparent half-life" of a drug. The apparent half life may be a
composite number that accounts for contributions from other
processes besides elimination, such as absorption, reuptake, or
enterohepatic recycling.
[0158] "Optional" or "optionally" means that the subsequently
described element, component or circumstance may or may not occur,
so that the description includes instances where the element,
component, or circumstance occurs and instances where it does
not.
[0159] "Partial AUC" means an area under the drug
concentration-time curve (AUC) calculated using linear trapezoidal
summation for a specified interval of time, for example, AUC(0-1
hr) AUC(0-2 hr), AUC(0-4 hr), AUC(0-6 hr), AUC(0-8 hr), AUC(0-(Tmax
of IR product+2SD)), AUC(0-(x)hr), AUC(x-yhr), AUC(Tmax-t),
AUC(0-(t)hr), AUC(Tmax of IR product+2SD)-t), or
AUC(0-.infin.).
[0160] A drug "release rate," as used herein, refers to the
quantity of drug released from a dosage form or pharmaceutical
composition per unit time, e.g., milligrams of drug released per
hour (mg/hr). Drug release rates for drug dosage forms are
typically measured as an in vitro rate of dissolution, i.e., a
quantity of drug released from the dosage form or pharmaceutical
composition per unit time measured under appropriate conditions and
in a suitable fluid. The specific results of dissolution tests
claimed herein are performed on dosage forms or pharmaceutical
compositions immersed in 900 mL of 0.1 N HCl using a USP Type II
apparatus at a paddle speed of either about 100 rpm or about 150
rpm and a constant temperature of about 37.degree. C. Suitable
aliquots of the release rate solutions are tested to determine the
amount of drug released from the dosage form or pharmaceutical
composition. For example, the drug can be assayed or injected into
a chromatographic system to quantify the amounts of drug released
during the testing intervals.
[0161] The terms "subject" or "patient" are used interchangeably
herein and refer to a vertebrate, preferably a mammal. Mammals
include, but are not limited to, humans.
[0162] The term "tap density" or "tapped density," as used herein,
refers to a measure of the density of a powder. The tapped density
of a pharmaceutical powder is determined using a tapped density
tester, which is set to tap the powder at a fixed impact force and
frequency. Tapped density by the USP method is determined by a
linear progression of the number of taps.
II. PHARMACEUTICAL COMPOSITIONS COMPRISING AN OPIOID AND AN
ADDITIONAL ACTIVE PHARMACEUTICAL INGREDIENT
[0163] The present disclosure provides pharmaceutical compositions
comprising at least one opioid (e.g., oxycodone) and its
pharmaceutical salts and at least one other active pharmaceutical
ingredient (API) (e.g., acetaminophen). It would be understood that
when present in a pharmaceutical composition, the opioid would be
in its salt form. For example, the pharmaceutical composition
comprises at least one extended release portion comprising
oxycodone, acetaminophen or a combination thereof, and an extended
release component. The pharmaceutical composition may also comprise
at least one immediate release portion comprising oxycodone,
acetaminophen, or a combination thereof. The compositions disclosed
herein are formulated to deliver therapeutic concentrations of
oxycodone and acetaminophen within about the first hour after oral
administration and to maintain therapeutic concentrations of
oxycodone and acetaminophen for an extended period of time (e.g.,
10-12 hours).
[0164] The present disclosure further provides for gastric
retentive, extended release compositions comprising at least one
opioid (e.g., oxycodone) and at least one other (API) (e.g.,
acetaminophen) that is preferably absorbed in the upper
gastrointestinal tract. In general, the gastric retentive, extended
release composition comprises at least one extended release
portion. The extended release portion(s) may comprise at least one
opioid, at least one API, or combinations thereof. The gastric
retentive, extended release composition disclosed herein may
further comprise at least one immediate release portion. The
immediate release portion(s) may comprise at least one opioid
(e.g., oxycodone), at least one other API (e.g., acetaminophen), or
combinations thereof.
(a) Active Agents
[0165] The composition disclosed herein comprises at least one
opioid and at least one additional API, each of which is discussed
in more detail below. In one embodiment, the same opioid or
combination of opioids is present in both the at least one
immediate release portion and the at least one extended release
portion of the composition; and the same API or combination of APIs
is present in both the at least one immediate release portion and
the at least one extended release portion of the composition.
[0166] (i) Opioids
[0167] The opioid(s) useful in the present invention include
adulmine, alfentanil, allocryptopine, allylprodine, alphaprodine,
anileridine, aporphine, benzylmorphine, berberine, bicuculine,
bicucine, bezitramide, buprenorphine, bulbocaprine, butorphanol,
clonitazene, codeine, desomorphine, dextromoramide, dezocine,
diampromide, diamorphone, dihydrocodeine, dihydromorphine,
dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl
butyrate, dipipanone, eptazocine, ethoheptazine,
ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl,
heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone,
ketobemidone, levorphanol, levophenacylmorphan, lofentanil,
meperidine, meptazinol, metazocine, methadone, metopon, morphine,
myrophine, narceine, nicomorphine, norlevorphanol, normethadone,
nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone,
oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan,
phenazocine, phenoperidine, piminodine, piritramide, propheptazine,
promedol, properidine, propoxyphene, sufentanil, tapentadol,
tilidine, tramadol, and pharmaceutical salts of any of the
foregoing.
[0168] In various embodiments, the extended release dosage form may
comprise one, two, three, four, or more than four opioids. In
another embodiment, the opioid is selected from the group
consisting of oxycodone, hydrocodone, tramadol, codeine, and
pharmaceutical salts of any of the foregoing. In yet another
embodiment, opioid is selected from the group consisting of
adulmine, alfentanil, allocryptopine, allylprodine, alphaprodine,
anileridine, aporphine, benzylmorphine, berberine, bicuculine,
bicucine, bezitramide, buprenorphine, bulbocaprine, butorphanol,
clonitazene, desomorphine, dextromoramide, dezocine, diampromide,
diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol,
dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate,
dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene,
ethylmorphine, etonitazene, fentanyl, heroin, hydromorphone,
hydroxypethidine, isomethadone, ketobemidone, levorphanol,
levophenacylmorphan, lofentanil, meperidine, meptazinol,
metazocine, methadone, metopon, morphine, myrophine, narceine,
nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene,
normorphine, norpipanone, opium, oxymorphone, papaveretum,
pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine,
piminodine, piritramide, propheptazine, promedol, properidine,
propoxyphene, sufentanil, tapentadol, tilidine, and pharmaceutical
salts of any of the foregoing. In one embodiment, the extended
release dosage form comprises one opioid. In a further embodiment,
the dosage form comprises oxycodone.
[0169] In one embodiment, the composition may comprise from about
1.0 mg to about 500 mg of the opioid. In another embodiment, the
composition may comprise from about 1.4 mg to about 400 mg of the
opioid. In yet another embodiment, the amount of opioid in the
composition may range from about 5 mg to about 300 mg. In still
another embodiment, the amount of opioid in the composition may
range from about 4 mg to about 30 mg. In another embodiment, the
amount of opioid in the composition may range from about 30 mg to
about 60 mg. In yet another embodiment, the amount of opioid in the
composition may range from about 60 mg to about 120 mg. In an
alternate embodiment, the amount of opioid in the composition may
range from about 120 mg to about 300 mg. In various embodiments,
the amount of opioid in the composition may be about 4 mg, 4.5 mg,
5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5
mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg,
19 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 30 mg, 32 mg, 34 mg, 36
mg, 38 mg, 40 mg, 42 mg, 44 mg, 46 mg, 48 mg, 50 mg, 52 mg, 54 mg,
56 mg, 58 mg, 60 mg, 62 mg, 64 mg, 66 mg, 68 mg, 70 mg, 80 mg, 90
mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg,
180 mg, 190 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320
mg, 340 mg, 360 mg, 380 mg, or 400 mg. In one embodiment, the
amount of opioid in the composition may range from about 7.5 mg to
about 30 mg. In another embodiment, the amount of opioid in the
composition may range from about 7.5 mg to about 15 mg. In still
another embodiment, the amount of opioid in the composition may
range from about 15 mg to about 30 mg.
[0170] In additional embodiments, the dosage form comprises
oxycodone, and the total amount of oxycodone present in the
pharmaceutical composition can and will vary. In some embodiments,
the total amount of oxycodone present in the pharmaceutical
composition may range from about 2 mg to about 160 mg, about 5 mg
to about 75 mg, about 5 mg to about 40 mg, or about 10 mg to about
30 mg. In another embodiment, the total amount of oxycodone in the
pharmaceutical composition may range from about 5 mg to about 30
mg. In additional embodiments, the total amount of oxycodone
present in the pharmaceutical composition may be about 5 mg, 5.5
mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg,
10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14
mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg,
18.5 mg, 19 mg, 19.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg,
32.5 mg, 35 mg, 37.5 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg,
100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, or 160 mg. In one
embodiment, the total amount of oxycodone in the pharmaceutical
composition may be about 30 mg. In another embodiment, the total
amount of oxycodone in the pharmaceutical composition may be about
15 mg. In still another embodiment, the total amount of oxycodone
in the pharmaceutical composition may be about 7.5 mg.
[0171] (ii) Other API
[0172] The composition disclosed herein may also comprise at least
one other API. In general, the other API is preferentially absorbed
in the upper gastrointestinal tract (GIT). Accordingly, optimal
absorption of the API may occur in the upper GIT (i.e., duodenum,
jejunum, and ileum of the small intestine), with little or no
absorption in the lower GIT (i.e., cecum and colon of the large
intestine).
[0173] In some embodiments, the other API may be a non-opioid
analgesic. Suitable non-opioid analgesics include acetaminophen
(also known as paracetamol), acetylsalicylic acid, diclofenac,
diflunisol, ibuprofen, indomethacin, ketoprofen, ketorolac,
naproxen, mefamanic acid, phenacetin, piroxicam, sulindac, and
tolmetin. In other embodiments, the other API may be a steroidal
anti-inflammatory agent such as celecoxib, deracoxib, ketoprofen,
lumiracoxib, meloxicam, parecoxib, rofecoxib, or valdecoxib. In a
further embodiment, the other API may be a steroidal
anti-inflammatory agent such as alclometasone, dexamethasone,
fluocinonide, hydrocortisone, methylprednisolone, prednisone,
prednisolone, or triamcinolone. In further embodiments, the other
API may be a norepinephrine transporter modulator such as
tapentadol, a tricyclic antidepressant such as amitriptyline, an
alpha-2 adrenergic agonist such as clonidine, a calcium channel
blocker such as nimodipine, a GABA B agonist such as baclofen, a
cannabinoid, a NMDA receptor antagonist, a CCK receptor antagonist,
a beta blocker, or a serotonin receptor antagonist. Any of the
aforementioned APIs may be in the form of a pharmaceutically
acceptable salt. In various embodiments, the at least one extended
release portion may comprise one, two, three, four, or more APIs.
In one embodiment, one extended release portion may comprise one of
the other APIs.
[0174] The amount of the other API in the gastric retentive,
extended release composition can and will vary. In one embodiment,
the composition may comprise from about 1.0 mg to about 1500 mg of
the API. In another embodiment, the amount of API in the
composition may range from about 100 mg to about 1000 mg. In still
another embodiment, the amount of API in the composition may range
from about 50 mg to about 500 mg. In another embodiment, the amount
of API in the composition may range from about 10 mg to about 100
mg. In yet another embodiment, the amount of API in the composition
may range from about 1.0 mg to about 10 mg. In one embodiment, the
amount of API in the composition may range from about 250 mg to
about 1300 mg. In another embodiment, the amount of API in the
composition may range from about 325 mg to about 650 mg. In still
another embodiment, the amount of API in the composition may range
from about 650 mg to about 1300 mg.
[0175] In additional embodiments, the dosage form comprises
acetaminophen, and the total amount of acetaminophen present in the
pharmaceutical composition can and will vary. In one embodiment,
the total amount of acetaminophen present in the pharmaceutical
composition may range from about 80 mg to about 1600 mg. In another
embodiment, the total amount of acetaminophen present in the
pharmaceutical composition may be about 250 mg to about 1300 mg. In
a further embodiment, the total amount of acetaminophen present in
the pharmaceutical composition may be about 300 mg to about 600 mg.
In yet another embodiment, the total amount of acetaminophen
present in the pharmaceutical composition may be about 325 mg to
about 650 mg. In another embodiment, the total amount of
acetaminophen present in the pharmaceutical composition may be
about 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325
mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg,
550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 1000 mg, or 1300 mg. In one
embodiment, the total amount of acetaminophen in the pharmaceutical
composition may be about 650 mg. In another embodiment, the total
amount of acetaminophen in the pharmaceutical composition may be
about 500 mg. In yet another embodiment, the total amount of
acetaminophen in the pharmaceutical composition may be about 325
mg.
(b) Immediate Release Portion
[0176] The pharmaceutical composition disclosed herein may comprise
at least one immediate release portion. In one embodiment, the at
least one immediate release portion may comprise oxycodone. In
another embodiment, the at least one immediate release portion may
comprise acetaminophen. In a further embodiment, the at least one
immediate release portion may comprise oxycodone and
acetaminophen.
[0177] The at least one immediate release portion of the
pharmaceutical composition is designed to release more than 80%,
more than 90%, or essentially all of the opioid(s) and/or the other
API(s) in the at least one immediate release portion(s) within
about one hour. In one embodiment, more than 80%, more than 90%, or
essentially all of the opioid(s) and/or the other API(s) in the at
least one immediate release portion(s) may be released in less than
about 45 minutes. In another embodiment, more than 80%, more than
90%, or essentially all of the opioid(s) and/or the other API(s) in
the at least one immediate release portion(s) may be released in
less that about 30 minutes. In a further embodiment, more than 80%,
more than 90%, or essentially all of the opioid(s) and/or the other
API(s) in the at least one immediate release portion(s) may be
released in less than about 20 minutes. In yet another embodiment,
more than 80%, more than 90%, or essentially all of the opioid(s)
and/or the other API(s) in the at least one immediate release
portion(s) may be released in less that about 15 minutes. In an
alternate embodiment, more than 80%, more than 90%, or essentially
all of the opioid(s) and/or the other API(s) in the at least one
immediate release portion(s) may be released in less that about 10
minutes. In yet another embodiment, more than 80%, more than 90%,
or essentially all of the opioid(s) and/or the other API(s) in the
at least one immediate release portion may be released in less that
about 5 minutes.
[0178] In some embodiments, the immediate release portion may be
part of or homogeneously mixed with the extended release
portion.
[0179] (i) Opioid(s)
[0180] At least one immediate release portion of the composition
may comprise at least one opioid. Suitable opioids are detailed
above in Section (II)(a)(i). In one embodiment, the opioid may be
codeine or a salt thereof. In another embodiment, the opioid may be
hydrocodone or a salt thereof. In yet another embodiment, the
opioid may be hydromorphone or a salt thereof. In still another
embodiment, the opioid may be morphine or a salt thereof. In a
further embodiment, the opioid may be oxymorphone or a salt
thereof. In an alternate embodiment, the opioid may be tramadol or
a salt thereof. In another embodiment, the opioid may be oxycodone
or a salt thereof.
[0181] The amount of opioid present in the at least one immediate
release portion of the pharmaceutical composition can and will
vary. In one embodiment, the amount of opioid in the at least one
immediate release portion may range from about 0.4 mg to about 100
mg. In another embodiment, the amount of opioid in the at least one
immediate release portion may range from about 1.25 mg to about 75
mg. In another embodiment, the amount of opioid in the at least one
immediate release portion may range from about 1 mg to about 20 mg.
In still another embodiment, the amount of opioid in the at least
one immediate release portion may range from about 0.5 mg to about
10 mg. In another embodiment, the amount of opioid in the at least
one immediate release portion may range from about 7.5 mg to about
15 mg. In yet another embodiment, the amount of opioid in the at
least one immediate release portion may range from about 15 mg to
about 30 mg. In an alternate embodiment, the amount of opioid in
the at least one immediate release portion may range from about 30
mg to about 75 mg. In various embodiments, the amount of opioid in
the at least one immediate release portion may be about 1.25 mg,
1.3 mg, 1.325 mg, 1.35 mg, 1.375 mg, 1.4 mg, 1.425 mg, 1.45 mg,
1.475 mg, 1.5 mg, 1.525 mg, 1.55 mg, 1.575 mg, 1.6 mg, 1.625 mg,
1.65 mg, 1.675 mg, 1.7 mg, 1.725 mg, 1.75 mg, 1.775 mg, 1.8 mg,
1.825 mg, 1.85 mg, 1.875 mg, 1.9 mg, 1.925 mg, 1.95 mg, 1.975 mg,
2.0 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3.0 mg, 3.25 mg, 3.5 mg, 3.75 mg,
4.0 mg, 4.25 mg, 4.5 mg, 4.75 mg, 5.0 mg, 5.25 mg, 5.5 mg, 5.75 mg,
6.0 mg, 6.25 mg, 6.5 mg, 6.75 mg, 7.0 mg, 7.25 mg, 7.5 mg, 7.75 mg,
8.0 mg, 8.25 mg, 8.5 mg, 8.75 mg, 9.0 mg, 9.25 mg, 9.5 mg, 9.75 mg,
10.0 mg, 0 mg, 12.0 mg, 13.0 mg, 14.0 mg, 15.0 mg, 20.0 mg, 25 mg,
30 mg, 35 mg or 40.0 mg. In one embodiment, the amount of opioid in
the at least one immediate release portion may range from about 1.0
mg and about 2.0 mg, for example, about 1.25 mg, or in another
example, about 1.875 mg. In yet another embodiment, the amount of
opioid in the at least one immediate release portion may range from
about 2.0 mg and about 3.0 mg, for example, about 2.25 mg, or in a
further example, about 2.5 mg. In an additional embodiment, the
amount of opioid in the at least one immediate release portion may
range from 3 mg and about 4.0 mg, for example, about 3.75 mg. In
another embodiment, the amount of opioid in the at least one
immediate release portion may range from 7.0 mg and about 8.0 mg,
for example, about 7.5 mg. In a further embodiment, the amount of
opioid in the at least one immediate release portion may range from
about 1.0 mg and about 5.0 mg. In yet another embodiment, the
amount of opioid in the at least one immediate release portion may
range from about 1.0 mg and about 4.5 mg. In another embodiment,
the amount of opioid in the at least one immediate release portion
may range from about 1.0 mg and about 4.0 mg. In still another
embodiment, the amount of opioid in the at least one immediate
release portion may range from about 1.0 mg and about 3.75 mg. In
yet another embodiment, the amount of opioid in the at least one
immediate release portion may range from about 1.0 mg and about 3.5
mg.
[0182] The amount of opioid present in the at least one immediate
release portion(s) may be expressed as a percentage (w/w) of the
total amount of opioid in the pharmaceutical composition. In one
embodiment, the at least one immediate release portion may comprise
from about 20% to about 40% (w/w) of the total amount of opioid
present in the pharmaceutical composition. In certain embodiments,
the percentage of opioid present in the at least one immediate
release portion of the pharmaceutical composition may be about 20%,
21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%,
34%, 35%, 36%, 37%, 38%, 39%, or 40% (w/w) of the total amount of
opioid present in the composition. In one embodiment, the
percentage of opioid present in the at least one immediate release
portion may range from about 20% to about 30% (w/w) of the total
amount of opioid present in the composition. In another embodiment,
the percentage of opioid present in the at least one immediate
release portion of the pharmaceutical composition may be about 25%
(w/w) of the total amount of opioid present in the pharmaceutical
composition.
[0183] The amount of opioid in the at least one immediate release
portion also may be expressed as a percentage (w/w) of the total
weight of the immediate release portion(s) of the pharmaceutical
composition. In one embodiment, the amount of opioid in an
immediate release portion may range from about 0.2% (w/w) to about
20% (w/w) of the total weight of such immediate release portion of
the pharmaceutical composition. In another embodiment, the amount
of opioid in an immediate release portion may range from about 0.5%
(w/w) to about 5% (w/w) of the total weight of such immediate
release portion. In various embodiments, an immediate release
portion may comprise an amount of opioid that is approximately
0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%,
1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%,
2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%,
4.25%, 4.5%, 4.75%, 5.0%, 5.25%, 5.5%, 5.75%, 6.0%, 6.25%, 6.5%,
6.75%, 7.0%, 7.25%, 7.5%, 7.75%, 8.0%, 8.25%, 8.5%, 8.75%, 9.0%,
9.25%, 9.5%, 9.75%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%,
19%, or 20% (w/w) of the total weight of such immediate release
portion of the pharmaceutical composition. In yet another
embodiment, the amount of opioid in an immediate release portion
may be about 0.5% (w/w) to about 1.0% (w/w) of the total weight of
such immediate release portion of the pharmaceutical
composition.
[0184] In some embodiments, the opioid in the at least one
immediate release portion(s) of the pharmaceutical composition may
be in the form of particles comprising opioid and at least one
excipient. The at least one immediate release portion, therefore,
may comprise particles of opioid(s) that are admixed with other
API(s) and optional excipient(s). Suitable oxycodone particles are
described in co-pending application U.S. application Ser. No.
13/166,770, filed Jun. 22, 2011, which is incorporated herein by
reference in its entirety. The opioid particles may be coated or
uncoated. The average size or average diameter of the particles may
vary. In general, the average diameter of the particles may range
from about 50 microns to about 2000 microns, from about 100 microns
to about 1000 microns, or from about 150 microns to about 200
microns. In one embodiment, the maximum diameter of about 50% of
the particles (d50) may be about 40 microns, 50 microns, 100
microns, 150 microns, 200 microns, 250 microns, 300 microns, 400
microns, or 500 microns. In another embodiment, the maximum
diameter of about 90% of the particles (d90) may be about 100
microns, 150 microns, 200 microns, 250 microns, 300 microns, 400
microns, or 500 microns.
[0185] In one embodiment, the opioid found in the at least one
immediate release portion of the pharmaceutical composition is
oxycodone. The amount of oxycodone in the at least one immediate
release portion of the pharmaceutical composition can and will
vary. In one embodiment, the amount of oxycodone in the at least
one immediate release portion may range from about 0.4 mg to about
100 mg. In an additional embodiment, the amount of oxycodone in the
at least one immediate release portion may range from about 1 mg to
about 40 mg. In a further embodiment, the amount of oxycodone in
the at least one immediate release portion of the pharmaceutical
composition may range from about 1 mg to about 7.5 mg. In another
embodiment, the amount of oxycodone in the at least one immediate
release portion may range from about 7.5 mg to about 15 mg. In yet
another embodiment, the amount of oxycodone in the at least one
immediate release portion may range from about 15 mg to about 40
mg. In various embodiments, the amount of oxycodone in the at least
one immediate release portion may be about 1.25 mg, 1.3 mg, 1.325
mg, 1.35 mg, 1.375 mg, 1.4 mg, 1.425 mg, 1.45 mg, 1.475 mg, 1.5 mg,
1.525 mg, 1.55 mg, 1.575 mg, 1.6 mg, 1.625 mg, 1.65 mg, 1.675 mg,
1.7 mg, 1.725 mg, 1.75 mg, 1.775 mg, 1.8 mg, 1.825 mg, 1.85 mg,
1.875 mg, 1.9 mg, 1.925 mg, 1.95 mg, 1.975 mg, 2.0 mg, 2.25 mg, 2.5
mg, 2.75 mg, 3.0 mg, 3.25 mg, 3.5 mg, 3.75 mg, 4.0 mg, 4.25 mg, 4.5
mg, 4.75 mg, 5.0 mg, 5.25 mg, 5.5 mg, 5.75 mg, 6.0 mg, 6.25 mg, 6.5
mg, 6.75 mg, 7.0 mg, 7.25 mg, 7.5 mg, 7.75 mg, 8.0 mg, 8.25 mg, 8.5
mg, 8.75 mg, 9.0 mg, 9.25 mg, 9.5 mg, 9.75 mg, 10.0 mg, 11.0 mg,
12.0 mg, 12.5 mg, 13.0 mg, 14.0 mg, 15.0 mg, 17.5 mg, 20.0 mg, 22.5
mg, 25 mg, 27.5 mg, 30 mg, 40.0 mg, 75 mg, or 100 mg. In one
embodiment, the amount of oxycodone in the at least one immediate
release portion may range from about 7.0 mg and about 8.0 mg, for
example, about 7.5 mg. In another embodiment, the amount of
oxycodone in the at least one immediate release portion may be
between about 3.0 mg and about 4.0 mg, for example, about 3.75 mg.
In still another embodiment, the amount of opioid in the at least
one immediate release portion may range from about 1.0 mg and about
2.0 mg, for example, about 1.875 mg. In a further embodiment, the
amount of oxycodone in the at least one immediate release portion
may range from about 1.0 mg and about 5.0 mg. In yet another
embodiment, the amount of oxycodone in the at least one immediate
release portion may range from about 1.0 mg and about 4.5 mg. In
another embodiment, the amount of oxycodone in the at least one
immediate release portion may range from about 1.0 mg and about 4.0
mg. In still another embodiment, the amount of oxycodone in the at
least one immediate release portion may range from about 1.0 mg and
about 3.5 mg. In yet another embodiment, the amount of oxycodone in
the at least one immediate release portion may range from about 1.0
mg and about 3.0 mg.
[0186] The amount of oxycodone present in the at least one
immediate release portion(s) may be expressed as a percentage (w/w)
of the total amount of oxycodone in the pharmaceutical composition.
In one embodiment, the at least one immediate release portion may
comprise from about 20% to about 40% (w/w) of the total amount of
oxycodone present in the pharmaceutical composition. In certain
embodiments, the percentage of oxycodone present in the at least
one immediate release portion of the pharmaceutical composition may
be about 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%,
31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, or 40% (w/w) of the
total amount of oxycodone. In another embodiment, the percentage of
oxycodone present in the at least one immediate release portion of
the pharmaceutical composition may be about 25% (w/w) of the total
amount of oxycodone present in the pharmaceutical composition.
[0187] The amount of oxycodone in the at least one immediate
release portion also may be expressed as a percentage (w/w) of the
total weight of the immediate release portion(s) of the
pharmaceutical composition. In one embodiment, the amount of
oxycodone in an immediate release portion may range from about 0.2%
(w/w) to about 20% (w/w) of the total weight of such immediate
release portion of the pharmaceutical composition. In another
embodiment, the amount of oxycodone in an immediate release portion
may range from about 0.5% (w/w) to about 5% (w/w) of the total
weight of such immediate release portion. In various embodiments,
an immediate release portion may comprise an amount of oxycodone
that is approximately 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%,
0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%,
2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%,
3.25%, 3.5%, 3.75%, 4.0%, 4.25%, 4.5%, 4.75%, 5.0%, 5.25%, 5.5%,
5.75%, 6.0%, 6.25%, 6.5%, 6.75%, 7.0%, 7.25%, 7.5%, 7.75%, 8.0%,
8.25%, 8.5%, 8.75%, 9.0%, 9.25%, 9.5%, 9.75%, 10%, 11%, 12%, 13%,
14%, 15%, 16%, 17%, 18%, 19%, or 20% (w/w) of the total weight of
such immediate release portion of the pharmaceutical composition.
In yet another embodiment, the amount of oxycodone in an immediate
release portion may be about 0.5% (w/w) to about 1.0% (w/w) of the
total weight of such immediate release portion of the
pharmaceutical composition.
[0188] In some embodiments, the oxycodone of the at least one
immediate release portion(s) of the pharmaceutical composition may
be in the form of particles comprising oxycodone and at least one
excipient. The at least one immediate release portion, therefore,
may comprise particles of oxycodone that are admixed with other
API(s), such as acetaminophen and optional excipient(s). Suitable
oxycodone particles are described in co-pending application U.S.
application Ser. No. 13/166,770, filed Jun. 22, 2011, which is
incorporated herein by reference in its entirety. The oxycodone
particles may be coated or uncoated. The average size or average
diameter of the particles may vary. In general, the average
diameter of the particles may range from about 50 microns to about
2000 microns, from about 100 microns to about 1000 microns, or from
about 150 microns to about 200 microns. In one embodiment, the
maximum diameter of about 50% of the particles (d50) may be about
40 microns, 50 microns, 100 microns, 150 microns, 200 microns, 250
microns, 300 microns, 400 microns, or 500 microns. In another
embodiment, the maximum diameter of about 90% of the particles
(d90) may be about 100 microns, 150 microns, 200 microns, 250
microns, 300 microns, 400 microns, or 500 microns.
[0189] (ii) Other API(s)
[0190] At least one immediate release portion of the composition
may comprise at least one other API. Examples of suitable APIs that
may be included in the at least one immediate release portion are
presented above in Section (II)(a)(ii). In one embodiment, the
other API may be acetylsalicylic acid or a salt thereof. In another
embodiment, the other API may be diclofenac or a salt thereof. In
yet another embodiment, the other API may be ibuprofen or a salt
thereof. In still another embodiment, the other API may be
indomethacin or a salt thereof. In a further embodiment, the other
API may be ketoprofen or a salt thereof. In an alternate
embodiment, the other API may be naproxen or a salt thereof. In
another embodiment, the other API may be piroxicam or a salt
thereof. In still another embodiment, the other API may be
prednisolone or a salt thereof. In one embodiment, the other API
may be acetaminophen or salt thereof.
[0191] The amount of the other API in the at least one immediate
release portion can and will vary. In one embodiment, the immediate
release portion may comprise from about 0.5 mg to about 750 mg of
the API. In another embodiment, the amount of API in the at least
one immediate release portion may range from about 50 mg to about
500 mg. In another embodiment, the amount of API in the at least
one immediate release portion may range from about 25 mg to about
250 mg. In another embodiment, the amount of API in the at least
one immediate release portion may range from about 150 mg to about
500 mg. In yet another embodiment, the amount of API in the at
least one immediate release portion may range from about 0.5 mg to
about 5 mg. In one embodiment, the amount of API in the at least
one immediate release portion may range from about 125 mg to about
650 mg. In another embodiment, the amount of API in the at least
one immediate release portion may range from about 162.5 mg to
about 325 mg. In still another embodiment, the amount of API in the
at least one immediate release portion may range from about 325 mg
to about 650 mg. In an additional embodiment, the amount of API in
the at least one immediate release portion may range from about 100
mg to about 400 mg. In still another embodiment, the amount of API
in the at least one immediate release portion may range from about
125 mg to about 325 mg.
[0192] The amount of other API in the at least one immediate
release portion of the pharmaceutical composition can and will
vary. In general, the amount of other API present in the at least
one immediate release portion may range from about 30% to about 70%
(w/w) of the total amount of other API in the composition. In one
embodiment, the amount of other API present in the at least one
immediate release portion ranges from about 40% to about 60% (w/w)
of the total amount of API in the composition. In various
embodiments, the at least one immediate release portion of the
composition may comprise about 30%, 31%, 32%, 33%, 34%, 35%, 36%,
37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%,
50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%,
63%, 64%, 65%, 66%, 67%, 68%, 69%, or 70% (w/w) of the total amount
of API in the composition.
[0193] The amount of other API in an immediate release portion of
the composition may range from about 15% to about 95% (w/w) of the
total weight of such immediate release portion of the composition.
In various embodiments, the amount of other API(s) in an immediate
release portion may be about 15%, 20%, 25%, 30%, 35%, 40%, 45%,
50%, 55%, 60%, 65%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%,
77%, 78%, 79%, 80%, 82%, 84%, 86%, 88%, 90%, 92%, or 95% (w/w) of
the total weight of such immediate release portion.
[0194] In embodiments in which the other API is acetaminophen, the
amount of acetaminophen in the at least one immediate release may
range from about 40 mg to about 800 mg. In still another
embodiment, the at least one immediate release portion of the
pharmaceutical composition may comprise from about 100 mg to about
600 mg of acetaminophen. In another embodiment, the at least one
immediate release portion may comprise from about 150 mg to about
400 mg of acetaminophen. In a further embodiment, the amount of
acetaminophen in the at least one immediate release portion may
range from about 160 mg to about 325 mg. In an additional
embodiment, the amount of acetaminophen in the at least one
immediate release portion may range from about 100 mg to about 400
mg. In still another embodiment, the amount of acetaminophen in the
at least one immediate release portion may range from about 125 mg
to about 325 mg. In yet another embodiment, the amount of
acetaminophen in the at least one immediate release portion may
range from about 125 mg to about 400 mg.
[0195] In yet another embodiment, the amount of acetaminophen in
the at least one immediate release portion may be about 120 mg, 125
mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 162.5
mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg,
205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245
mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg,
290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330
mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg,
375 mg, 380 mg, 385 mg, 390 mg, 395 mg, 400 mg, 500 mg, 520 mg, 600
mg, 650 mg, 700 mg, 750 mg, or 780 mg. In one embodiment, the at
least one immediate release portion may comprise about 325 mg of
acetaminophen. In another embodiment, the amount of acetaminophen
in the at least one immediate release portion may be about 250 mg.
In yet another embodiment, the amount of acetaminophen in the at
least one immediate release portion may be about 162.5 mg. In still
another embodiment, the amount of acetaminophen in the at least one
immediate release portion may be about 125 mg.
[0196] The at least one immediate release portion(s) of the
pharmaceutical composition may comprise from about 40% to about 60%
(w/w) of the total amount of acetaminophen present in the
pharmaceutical composition. The amount of acetaminophen in the at
least one immediate release portion may be about 40%, 41%, 42%,
43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%,
56%, 57%, 58%, 59%, or 60% (w/w) of the total amount of
acetaminophen present in the pharmaceutical composition. In one
embodiment, the percentage of acetaminophen present in the at least
one immediate release portion may be about 50% (w/w) of the total
amount of acetaminophen present in the pharmaceutical
composition.
[0197] The amount of acetaminophen in an immediate release
portion(s) of the pharmaceutical composition may range from about
20% (w/w) to about 95% (w/w) of the total weight of such immediate
release portion of the composition. In various embodiments, an
immediate release portion may comprise an amount of acetaminophen
that is approximately about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%,
60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%,
73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%,
86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, or 95% (w/w) of the
total weight of such immediate release portion. In one embodiment,
the amount of acetaminophen in an immediate release portion may
range from about 70% to about 80% (w/w) of the total weight of such
immediate release portion of the pharmaceutical composition.
[0198] (iii) Excipients
[0199] The at least one immediate release portion(s) of
pharmaceutical composition may further comprise at least one
excipient. Suitable excipients include binders, fillers,
disintegrants, lubricants, antioxidants, chelating agents, and
color agents.
[0200] In one embodiment, the at least one immediate release
portion(s) of the pharmaceutical composition may comprise at least
one binder. Suitable binders include, without limit, starches
(including corn starch and pregelatinized starch), gelatin, sugars
(including sucrose, glucose, dextrose and lactose), polyethylene
glycol, polyols, polyvinylalcohols, C12-C18 fatty acid alcohols,
waxes, gums (e.g., guar gum, arabic gum, acacia gum, xantham gum,
etc.), gelatin, pectin, sodium alginate, polyvinylpyrrolidone,
cellulosic polymers (including hydroxypropyl cellulose,
hydroxypropyl methylcellulose, hydroxylcellulose, methylcellulose,
microcrystalline cellulose, ethylcellulose, hydroxyethyl cellulose,
and the like), polyacrylamides, and polyvinyloxoazolidone. In one
embodiment, the amount of binder or binders in an immediate release
portion of the pharmaceutical composition may range from about 5%
to about 10% (w/w) of the total weight of such immediate release
portion. In various embodiments, an immediate release portion of
the pharmaceutical composition may comprise at least one binder
that is present in an amount that is about 5.0%, 5.25%, 5.5%,
5.75%, 6.0%, 6.25%, 6.5%, 6.75%, 7.0%, 7.1%, 7.2%, 7.3%, 7.4%,
7.5%, 7.6%, 7.7%, 7.8%, 7.9%, 8.0%, 8.1%, 8.2%, 8.3%, 8.4%, 8.5%,
8.6%, or 8.7%, 8.8%, 8.9%, or 9.0% (w/w) of such immediate release
portion of the composition.
[0201] In another embodiment, the at least one immediate release
portion(s) of the pharmaceutical composition may comprise at least
one filler. Suitable fillers include but are not limited to
microcrystalline cellulose (MCC), dibasic calcium phosphate,
tribasic calcium phosphate, magnesium carbonate, magnesium oxide,
calcium silicate, magnesium aluminum silicate, silicon dioxide,
titanium dioxide, alumina, talc, kaolin, polyvinylpyrrolidone,
dibasic calcium sulfate, tribasic calcium sulfate, starch, calcium
carbonate, magnesium carbonate, carbohydrates, modified starches,
lactose, sucrose, dextrose, mannitol, sorbitol, and inorganic
compounds. In one embodiment, the amount of filler or fillers in an
immediate release portion may range from about 1.0% to about 10.0%
(w/w) of the total weight of such immediate release portion. In
various embodiments, an immediate release portion of the
pharmaceutical composition may comprise at least one filler that is
present in an amount that is about 1.0%, 1.5%, 2.0%, 2.5%, 3.0%,
3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.1%, 6.2%, 6.3%, 6.4%, 6.5%,
6.6%, 6.7%, 6.8%, 6.9%, 7.0%, 7.1%, 7.2%, 7.3%, 7.4%, 7.5%, 7.6%,
7.7%, 7.8%, 7.9%, 8.0%, 8.1%, 8.2%, 8.3%, 8.4%, 8.5%, 8.6%, 8.7%,
8.8%, 8.9%, 9.0%, 9.1%, 9.2%, 9.3%, 9.4%, 9.5%, 9.6%, 9.7%, 9.8%,
9.9%, or 10.0%, (w/w), of such immediate release portion of the
pharmaceutical composition.
[0202] In still another embodiment, the at least one immediate
release portion(s) of the pharmaceutical composition may further
comprise at least one disintegrant. The disintegrant may be
selected from the group consisting of croscarmellose sodium,
crospovidone, alginic acid, carboxymethylcellulose calcium,
carboxymethylcellulose sodium, low substituted
hydroxypropylcellulose, microcrystalline cellulose, and sodium
starch glycolate. In one embodiment, the amount of disintegrant in
an immediate release portion may range from about 2.0% to about
15.0% (w/w) of the total weight of such immediate release portion.
In some embodiments, the amount of disintegrant in an immediate
release portion may be about 4.0%, 4.2%, 4.4%, 4.6%, 4.8%, 5.0%,
5.2%, 5.4%, 5.6%, 5.8%, 6.0%, 6.2%, 6.4%. 6.6%, 6.8%, or 7.0% (w/w)
of such immediate release portion of the pharmaceutical
composition.
[0203] In a further embodiment, the at least one immediate release
portion(s) of the pharmaceutical composition may further comprise a
lubricant. Useful lubricants include magnesium stearate, calcium
stearate, stearic acid, and hydrogenated vegetable oil (preferably
comprised of hydrogenated and refined triglycerides of stearic and
palmitic acids). The lubricant may be present in an amount ranging
from about 0.1% to about 3.0% (w/w) of the total weight of an
immediate release portion. In certain embodiments, the amount of
lubricant in at least one immediate release portion may be about
0.25%, 0.5%, 0.75%, 1.0%, 1.5%, 1.55%, 1.6%, 1.65%, 1.7%, 1.75%,
1.80%, 1.85%, 1.90%, 1.95%, or 2.0% (w/w) of the total weight of
such immediate release portion.
[0204] In yet another embodiment, the at least one immediate
release portion(s) of the pharmaceutical composition may comprise
at least one antioxidant. Suitable antioxidants include, without
limitation, ascorbic acid, citric acid, ascorbyl palmitate,
butylated hydroxyanisole, a mixture of 2 and 3
tertiary-butyl-4-hydroxyanisole, butylated hydroxytoluene, sodium
isoascorbate, dihydroguaretic acid, potassium sorbate, sodium
bisulfate, sodium metabisulfate, sorbic acid, potassium ascorbate,
vitamin E, 4-chloro-2,6-ditertiarybutylphenol, alphatocopherol, and
propylgallate. The amount of antioxidant present in an immediate
release portion of the pharmaceutical composition may range from
about 0.01% to about 4.0% (w/w), or from about 0.02% to about 0.10%
(w/w) of the total weight of such immediate release portion. In
various embodiments, the amount of antioxidant present in an
immediate release portion of the pharmaceutical composition may be
about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%,
0.09%, 0.10%, 0.12%, 0.14%, 0.16%, 0.18%, 0.20%, 0.25%, 0.50%,
0.75%, 1.00%, 1.50%, or 2.00% (w/w) of the total weight of such
immediate release portion.
[0205] In still another embodiment, the at least one immediate
release portion(s) of the pharmaceutical composition may comprise
at least one chelating agent. Suitable chelating agents include
ethylenediamine tetracetic acid (EDTA) and its salts,
N-(hydroxy-ethyl)ethylenediaminetriacetic acid, nitrilotriacetic
acid (NIA), ethylene-bis(oxyethylene-nitrilo)tetraacetic acid,
1,4,7,10-tetraazacyclodo-decane-N,N',N'',N'''-tetraacetic acid,
1,4,7,10-tetraaza-cyclododecane-N,N',N''-triacetic acid,
1,4,7-tris(carboxymethyl)-10-(2'-hydroxypropyl)-1,4,7,10-tetraazocyclodec-
ane, 1,4,7-triazacyclonane-N,N',N''-triacetic acid,
1,4,8,11-tetraazacyclotetra-decane-N,N',N'',N'''-tetraacetic acid;
diethylenetriamine-pentaacetic acid (DTPA), ethylenedicysteine,
bis(aminoethanethiol)carboxylic acid,
triethylenetetraamine-hexaacetic acid, and
1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid. In one
embodiment, the chelating agent may be the sodium salt of EDTA. The
amount of chelating agent present in an immediate release portion
of the pharmaceutical composition may range from about 0.001% to
about 0.20% (w/w) of such immediate release portion. In some
embodiments, the amount of chelating agent present in an immediate
release portion of the pharmaceutical composition may be about
0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%,
0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%,
0.14%, or 0.15% (w/w) of the total weight of such immediate release
portion.
[0206] In an alternate embodiment, the at least one immediate
release portion of the pharmaceutical composition may comprise a
color agent. Suitable color additives include, but are not limited
to, food, drug and cosmetic colors (FD&C), drug and cosmetic
colors (D&C), and external drug and cosmetic colors (Ext.
D&C). In various embodiments, the amount of color agent present
in an immediate release portion may range from about 2.0% to about
5.0% (w/w) of the total weight of such immediate release portion of
the composition. In other embodiments, the amount of color agent
present in an immediate release portion may be about 1.0%, 1.5%,
2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, or 5.0% (w/w) of the total
weight of such immediate release portion.
(c) Extended Release Portion
[0207] The pharmaceutical composition disclosed herein comprises at
least one extended release portion. The at least one extended
release portion may comprise at least one opioid, such as
oxycodone, at least one other API, such as acetaminophen, or
combinations thereof. The at least one extended release portion(s)
further comprises at least one extended release component. The
extended release component may comprise at least one extended
release polymer.
[0208] The at least one extended release portion of the
pharmaceutical composition is designed to release the active agents
over an extended period of time. In general, the at least one
extended release portion(s) provides release of the opioid(s), such
as oxycodone, and/or the API(s), such as acetaminophen, for a
period of time ranging from at least about 3 hours (hrs) to at
least about 12 hrs. In one embodiment, the opioid(s) and/or the
other API(s) may be released from the at least one extended release
portion over a period of at least about 5 hours (hrs), or over a
period of at least about 6 hours (hrs). In another embodiment, the
at least one extended release portion may release the opioid(s)
and/or the other API(s) over a period of at least about 7 hours
(hrs), or over a period of at least about 8 hours (hrs). In still
another embodiment, the opioid(s) and/or the other API(s) may be
released from the at least one extended release portion over a
period of at least about 9 hours (hrs), or over a period of at
least about 10 hours (hrs). In a further embodiment, the at least
one extended release portion may release the opioid(s) and/or the
other API(s) over a period of at least about 11 hours (hrs), or
over a period of at least about 12 hours (hrs).
[0209] (i) Opioids
[0210] At least one extended release portion of the pharmaceutical
composition comprises at least one opioid. Suitable opioids are
detailed above in Section (II)(a)(i). In one embodiment, the opioid
may be codeine or a salt thereof. In another embodiment, the opioid
may be hydrocodone or a salt thereof. In yet another embodiment,
the opioid may be hydromorphone or a salt thereof. In still another
embodiment, the opioid may be morphine or a salt thereof. In a
further embodiment, the opioid may be oxymorphone or a salt
thereof. In an alternate embodiment, the opioid may be tramadol or
a salt thereof. In another embodiment, the opioid may be oxycodone
or a salt thereof.
[0211] The amount of opioid present in the at least one extended
release portion(s) can and will vary. In one embodiment, the amount
of opioid in the at least one extended release portion may range
from about 1 mg to about 300 mg. In another embodiment, the amount
of opioid in the at least one extended release portion may range
from about 3.75 mg to about 225 mg. In yet another embodiment, the
amount of opioid in the at least one extended release portion may
range from about 3.75 mg to about 120 mg. In a further embodiment,
the at least one extended release portion of the pharmaceutical
composition may comprise from about 1 mg to about 22.5 mg of
opioid. In an additional embodiment, the at least one extended
release portion of the pharmaceutical composition may comprise from
about 1 mg to about 15 mg of opioid. In another embodiment, the
amount of opioid in the at least one extended release portion may
be from about 22.5 mg to about 45 mg. In yet another embodiment,
the amount opioid in the at least one extended release portion may
be from about 45 mg to about 90 mg. In still another embodiment,
the amount of opioid in the at least one extended release portion
may be from about 90 mg to about 225 mg. In yet another embodiment,
the amount of opioid in the at least one extended release portion
may be about 10 mg to about 30 mg. In yet another embodiment, the
amount of opioid in the at least one extended release portion may
be about 30 mg to about 60 mg.
[0212] In one embodiment, the amount of opioid in the at least one
extended release portion may be from about 22 mg to about 23 mg,
for example, about 22.5 mg. In another embodiment, the amount of
opioid in the at least one extended release portion may be about 10
mg to about 12 mg, for example, about 11.25 mg.
[0213] In a further embodiment, the amount of opioid in the at
least one extended release portion may be about 5.625 mg. In an
additional embodiment, the amount of opioid in the at least one
extended release portion may be about 10 mg to about 12.5 mg. In a
further embodiment, the amount of opioid in the at least one
extended release portion may be about 12 mg to about 18 mg. In
another embodiment, the amount of opioid in the at least one
extended release portion may be about 20 mg to about 25 mg. In a
yet another embodiment, the amount of opioid in the at least one
extended release portion may be about 2.5 mg to about 12.5 mg. In a
further embodiment, the amount of opioid in the at least one
extended release portion may be about 3 mg to about 8 mg. In
another embodiment, the at least one extended release portion
comprises about 5 mg to about 7 mg of opioid. In a further
embodiment, the amount of opioid may be about 5.625 mg to about
11.25 mg. In a yet another embodiment, the amount of opioid in the
at least one extended release portion may be about 3.75 mg. In a
yet another embodiment, the amount of opioid in the at least one
extended release portion may be about 5.625 mg. In still another
embodiment, the amount of opioid in the at least one extended
release portion may be about 7.5 mg. In still another embodiment,
the amount of opioid in the at least one extended release portion
may be about 11.25 mg. In an additional embodiment, the amount of
opioid in the at least one extended release portion may be about
2.0 mg to about 7.0 mg. In a further embodiment, the amount of
opioid in the at least one extended release portion may be about
3.0 mg to about 7.0 mg. In still a further embodiment, the amount
of opioid in the at least one extended release portion may be about
4.0 mg to about 7.0 mg. In a another embodiment, the amount of
opioid in the at least one extended release portion may be about
4.0 mg to about 6.5 mg. In yet another embodiment, the amount of
opioid in the at least one extended release portion may be about
4.5 mg to about 6.5 mg.
[0214] In yet another embodiment, the amount of opioid in the at
least one extended release portion may be about 1.0 mg, 1.5 mg, 2.0
mg, 2.5 mg, 3.0 mg, 3.5 mg, 3.75 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5
mg, 5.625 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0
mg, 9.5 mg, 10.0 mg, 10.5 mg, 11.0 mg, 11.25 mg, 11.5 mg, 12.0 mg,
12.5 mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 16.0
mg, 16.5 mg, 17.0 mg, 17.5 mg, 18.0 mg, 18.5 mg, 19.0 mg, 19.5 mg,
20.0 mg, 22.5 mg, or 25 mg, 27.5 mg, 30 mg, 35 mg, 40 mg, 45 mg, or
50 mg.
[0215] The amount of opioid present in the at least one extended
release portion(s) may be expressed as a percentage of the total
amount of opioid in the pharmaceutical composition. In one
embodiment, the at least one extended release portion of the
pharmaceutical composition comprises from about 60% to about 80%
(w/w) of the total amount of opioid present in the pharmaceutical
composition. In certain embodiments, the percentage of opioid
present in the at least one extended release portion of the
pharmaceutical composition may be about 60%, 61%, 62%, 63%, 64%,
65%, 66%, 67%, 68%, 69% 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%,
78%, 79%, or 80% (w/w) of the total amount of opioid present in the
composition. In one embodiment, the percentage of opioid present in
the at least one extended release portion of the pharmaceutical
composition may be about 75% of the total amount of opioid present
in the pharmaceutical composition.
[0216] The amount of opioid in the extended release portion(s) also
may be expressed as a percentage of the total weight of the
extended release portion(s) of the pharmaceutical composition. In
one embodiment, the amount of opioid in an extended release portion
may range from about 0.3% to about 8.0% (w/w) of the total weight
of the extended release portion of the pharmaceutical composition.
In various embodiments, an extended release portion may comprise an
amount of opioid that is approximately 0.3%, 0.4%, 0.5%, 0.6%,
0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%,
1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%,
2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%,
or 4.0%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, or 8% (w/w) of the
total weight of such extended release portion of the pharmaceutical
composition. In one embodiment, the amount of opioid in an extended
release portion comprises about 0.5% to about 2% (w/w) of the total
weight of such extended release portion of the pharmaceutical
composition.
[0217] In some embodiments, the opioid of the at least one extended
release portion of the composition(s) may be in the form of
particles comprising the opioid and at least one excipient. Thus,
the at least one extended release portion may comprise particles of
opioid(s) which are admixed with the additional API(s), such as
acetaminophen, and the extended release component, both of which
are detailed below, as well as optional excipient(s). Suitable
oxycodone particles are described in co-pending application U.S.
application Ser. No. 13/166,770, filed Jun. 22, 2011, which is
incorporated herein by reference in its entirety. The opioid
particles may be coated or uncoated. The average size or average
diameter of the particles may vary. In general, the average
diameter of the particles may range from about 50 microns to about
2000 microns, from about 100 microns to about 1000 microns, or from
about 150 microns to about 200 microns. In one embodiment, the
maximum diameter of about 50% of the particles (d50) may be about
40 microns, 50 microns, 100 microns, 150 microns, 200 microns, 250
microns, 300 microns, 400 microns, or 500 microns. In another
embodiment, the maximum diameter of about 90% of the particles
(d90) may be about 100 microns, 150 microns, 200 microns, 250
microns, 300 microns, 400 microns, or 500 microns.
[0218] In embodiments in which the opioid is oxycodone, the amount
of oxycodone in the at least one extended release portion(s) can
and will vary. In one embodiment, the amount of oxycodone in the at
least one extended release portion may range from about 1 mg to
about 300 mg. In another embodiment, the amount of opioid in the at
least one extended release portion may range from about 3.75 mg to
about 225 mg. In another embodiment, the amount of opioid in the at
least one extended release portion may range from about 3.75 mg to
about 120 mg. In still another embodiment, the amount of opioid in
the at least one extended release portion may range from about 45
mg to about 90 mg.
[0219] In a further embodiment, the at least one extended release
portion of the pharmaceutical composition may comprise from about 1
mg to about 22.5 mg of oxycodone. In another embodiment, the amount
of in the at least one extended release portion may be about 10 mg
to about 30 mg. In yet another embodiment, the amount of oxycodone
in the at least one extended release portion may be about 30 mg to
about 60 mg. In still another embodiment, the amount of oxycodone
in the at least one extended release portion may be about 22.5 mg
to about 45 mg. In another embodiment, the at least one extended
release portion comprises about 5 mg to about 7 mg of oxycodone. In
a further embodiment, the amount of oxycodone may be about 5.625 mg
to about 11.25 mg. In an additional embodiment, the amount of
oxycodone may be about 10 mg to about 12.5 mg. In a further
embodiment, the amount of oxycodone may be about 12 mg to about 18
mg. In another embodiment, the amount of oxycodone in the at least
one extended release portion may be about 20 mg to about 25 mg. In
an additional embodiment, the amount of oxycodone may be about 2.0
mg to about 7.0 mg. In a further embodiment, the amount of
oxycodone may be about 3.0 mg to about 7.0 mg. In still a further
embodiment, the amount of oxycodone may be about 4.0 mg to about
7.0 mg. In a another embodiment, the amount of oxycodone may be
about 4.0 mg to about 6.5 mg. In yet another embodiment, the amount
of oxycodone may be about 4.5 mg to about 6.5 mg.
[0220] In yet another embodiment, the amount of oxycodone may be
about 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5
mg, 5.0 mg, 5.5 mg, 5.625 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0
mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0 mg, 10.5 mg, 11.0 mg, 11.25 mg,
11.5 mg, 12.0 mg, 12.5 mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0
mg, 15.5 mg, 16.0 mg, 16.5 mg, 17.0 mg, 17.5 mg, 18.0 mg, 18.5 mg,
19.0 mg, 19.5 mg, 20.0 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 35 mg,
40 mg, 45 mg, or 50 mg. In one embodiment, the amount of oxycodone
in the at least one extended release portion may be from about 22
mg to about 23 mg, for example, about 22.5 mg. In another
embodiment, the amount of oxycodone in the at least one extended
release portion may be about 10 mg to about 12 mg, for example,
about 11.25 mg. In still another embodiment, the amount of
oxycodone in the at least one extended release portion may be from
about 5 mg to about 6 mg, for example, about 5.625 mg.
[0221] The amount of oxycodone present in the at least one extended
release portion(s) may be expressed as a percentage of the total
amount of oxycodone in the pharmaceutical composition. In one
embodiment, the at least one extended release portion of the
pharmaceutical composition comprises from about 60% to about 80%
(w/w) of the total amount of oxycodone present in the
pharmaceutical composition. In certain embodiments, the percentage
of oxycodone present in the at least one extended release portion
of the pharmaceutical composition may be about 60%, 61%, 62%, 63%,
64%, 65%, 66%, 67%, 68%, 69% 70%, 71%, 72%, 73%, 74%, 75%, 76%,
77%, 78%, 79%, or 80% (w/w) of the total amount of oxycodone
present in the composition. In one embodiment, the percentage of
oxycodone present in the at least one extended release portion of
the pharmaceutical composition may be about 75% of the total amount
of oxycodone present in the pharmaceutical composition.
[0222] The amount of oxycodone in the extended release portion(s)
also may be expressed as a percentage of the total weight of the
extended release portion(s) of the pharmaceutical composition. In
one embodiment, the amount of oxycodone in an extended release
portion may range from about 0.3% to about 8.0% (w/w) of the total
weight of the extended release portion of the pharmaceutical
composition. In various embodiments, an extended release portion
may comprise an amount of oxycodone that is approximately 0.3%,
0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%,
1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%,
2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%,
3.7%, 3.8%, 3.9%, or 4.0%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, or
8% (w/w) of the total weight of such extended release portion of
the pharmaceutical composition. In one embodiment, the amount of
oxycodone in an extended release portion comprises about 0.5% to
about 2% (w/w) of the total weight of such extended release portion
of the pharmaceutical composition.
[0223] In some embodiments, the oxycodone of the at least one
extended release portion of the composition(s) may be in the form
of particles comprising oxycodone and at least one excipient. Thus,
the at least one extended release portion may comprise particles of
oxycodone which are admixed with the additional API(s), such as
acetaminophen and the extended release component, both of which are
detailed below, as well as optional excipients. Suitable oxycodone
particles are described in co-pending application U.S. application
Ser. No. 13/166,770, filed Jun. 22, 2011, which is incorporated
herein by reference in its entirety. The oxycodone particles may be
coated or uncoated. The average size or average diameter of the
particles may vary. In general, the average diameter of the
particles may range from about 50 microns to about 2000 microns,
from about 100 microns to about 1000 microns, or from about 150
microns to about 200 microns. In one embodiment, the maximum
diameter of about 50% of the particles (d50) may be about 40
microns, 50 microns, 100 microns, 150 microns, 200 microns, 250
microns, 300 microns, 400 microns, or 500 microns. In another
embodiment, the maximum diameter of about 90% of the particles
(d90) may be about 100 microns, 150 microns, 200 microns, 250
microns, 300 microns, 400 microns, or 500 microns.
[0224] (ii) Other API(s)
[0225] The at least one extended release portion of the
pharmaceutical composition may comprise at least one other API.
Examples of suitable APIs that may be included in the at least one
extended release portion are presented above in Section (I)(a)(ii).
In one embodiment, the other API may be acetylsalicylic acid or a
salt thereof. In another embodiment, the API may be diclofenac or a
salt thereof. In yet another embodiment, the API may be ibuprofen
or a salt thereof. In still another embodiment, the API may be
indomethacin or a salt thereof. In a further embodiment, the API
may be ketoprofen or a salt thereof. In an alternate embodiment,
the API may be naproxen or a salt thereof. In another embodiment,
the API may be piroxicam or a salt thereof. In still another
embodiment, the API may be prednisolone or a salt thereof. In one
embodiment, the API may be acetaminophen or salt thereof.
[0226] The amount of the other API in the at least one extended
release portion can and will vary. In one embodiment, the at least
one extended release portion may comprise from about 0.5 mg to
about 750 mg of the API. In another embodiment, the amount of API
in the at least one extended release portion may range from about
50 mg to about 500 mg. In another embodiment, the amount of API in
the at least one extended release portion may range from about 25
mg to about 250 mg. In another embodiment, the amount of API in the
at least one extended release portion may range from about 150 mg
to about 500 mg. In yet another embodiment, the amount of API in
the at least one extended release portion may range from about 0.5
mg to about 5 mg. In one embodiment, the amount of API in the at
least one extended release portion may range from about 125 mg to
about 650 mg. In another embodiment, the amount of API in the at
least one extended release portion may range from about 162.5 mg to
about 325 mg. In still another embodiment, the amount of API in the
at least one extended release portion may range from about 325 mg
to about 650 mg. In yet another embodiment, the amount of API in
the at least one extended release portion may range from about 100
mg to about 400 mg. In an additional embodiment, the amount of API
in the at least one extended release portion may range from about
125 mg to about 325 mg.
[0227] The amount of other API(s) in the at least one extended
release portion of the pharmaceutical composition can and will
vary, depending upon the identity of the API(s). In general, the
amount of other API present in the at least one extended release
portion may range from about 30% to about 70% (w/w) of the total
amount of other API in the composition. In one embodiment, the
amount of other API present in the at least one extended release
portion may range from about 40% to about 60% (w/w) of the total
amount of other API in the composition. In various embodiments, the
at least one extended release portion of the pharmaceutical
composition may comprise about 30%, 31%, 32%, 33%, 34%, 35%, 36%,
37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%,
50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%,
63%, 64%, 65%, 66%, 67%, 68%, 69%, or 70% (w/w) of the total amount
of other API in the composition.
[0228] The amount of other API in an extended release portion also
may be expressed as a percentage of the total weight of such
extended release portion of the pharmaceutical composition. In
various embodiments, the amount of other API in an extended release
portion may range from about 10% to about 70% (w/w) of the total
weight of such extended release portion of the composition. In
various embodiments, the amount of other API in an extended release
portion may be about 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%,
19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 32%,
34%, 36%, 38%, 40%, 42%, 44%, 46%, 48%, 50%, 52%, 54%, 56%, 58%,
60%, 62%, 64%, 66%, 68%, or 70% (w/w) of the total weight of such
extended release portion of the composition.
[0229] In embodiments in which the other API is acetaminophen, the
amount of acetaminophen in the at least one extended release
portion may range from about 40 mg to about 800 mg. In still
another embodiment, the at least one extended release portion of
the pharmaceutical composition may comprise from about 100 mg to
about 600 mg of acetaminophen. In another embodiment, the at least
one extended release portion may comprise from about 125 mg to
about 400 mg of acetaminophen. In a further embodiment, the amount
of acetaminophen in the at least one extended release portion may
range from about 160 mg to about 325 mg. In yet another embodiment,
the amount of acetaminophen in the at least one extended release
portion may range from about 100 mg to about 400 mg. In an
additional embodiment, the amount of acetaminophen in the at least
one extended release portion may range from about 125 mg to about
325 mg.
[0230] In yet another embodiment, the amount of acetaminophen in
the at least one extended release portion may be about 100 mg, 110
mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg,
160 mg, 162.5 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg,
195 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270
mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 325 mg, 330 mg, 340 mg,
350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 450 mg, 500 mg, 520
mg, 550 mg, 600 mg, 625 mg, 650 mg, 700 mg, 750 mg, 775 mg, 780 mg,
or 800 mg. In one embodiment, the at least one extended release
portion comprises about 325 mg of acetaminophen. In another
embodiment, the amount of acetaminophen in the at least one
extended release portion may be about 250 mg. In yet another
embodiment, the amount of acetaminophen in the at least one
extended release portion may be about 162.5 mg. In still another
embodiment, the amount of acetaminophen in the at least one
extended release portion may be about 125 mg.
[0231] The amount of acetaminophen in the at least one extended
release portion(s) of the pharmaceutical composition may comprise
from about 40% to about 60% of the total amount of acetaminophen
present in the pharmaceutical composition. The amount of
acetaminophen in the at least one extended release portion may be
about 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%,
52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, or 60% (w/w) of the total
amount of acetaminophen present in the pharmaceutical composition.
In one embodiment, the percentage of acetaminophen present in the
at least one extended release portion(s) of the pharmaceutical
composition may be about 50% (w/w) of the total amount of
acetaminophen present in the composition.
[0232] The amount of acetaminophen in an extended release portion
of the pharmaceutical composition may range from about 15% to about
60% (w/w) of the total weight of such extended release portion of
the pharmaceutical composition. In various embodiments, the amount
of acetaminophen in an extended release portion may comprise an
amount of acetaminophen that is approximately about 15%, 16%, 17%,
18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%,
32%, 35%, 37%, 40%, 42%, 45%, 47%, 50%, 52%, 55%, 57%, or 60% (w/w)
of the total weight of such extended release portion. In one
embodiment, the amount of acetaminophen in an extended release
portion may range from about 20% to about 40% (w/w) of the total
weight of such extended release portion of the pharmaceutical
composition.
[0233] (iii) Extended Release Component
[0234] The extended release portion(s) of the composition also
comprise(s) an extended release component. Suitable extended
release components include polymers, resins, hydrocolloids,
hydrogels, and the like.
[0235] In one embodiment, the extended release component may
comprise at least one extended release polymer. Suitable polymers
for inclusion in the at least one extended release portion of the
composition may be linear, branched, dendrimeric, or star polymers,
and include synthetic hydrophilic polymers as well as
semi-synthetic and naturally occurring hydrophilic polymers. The
polymers may be homopolymers or copolymers, such as random
copolymers, block copolymers, and graft copolymers. Suitable
hydrophilic polymers include, but are not limited to: polyalkylene
oxides, particularly poly(ethylene oxide), polyethylene glycol and
poly(ethylene oxide)-poly(propylene oxide) copolymers; cellulosic
polymers, such as methylcellulose, hydroxymethylcellulose,
hydroxyethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, and carboxymethylcellulose,
microcrystalline cellulose, and polysaccharides and their
derivatives; acrylic acid and methacrylic acid polymers, copolymers
and esters thereof, preferably formed from acrylic acid,
methacrylic acid, methyl acrylate, ethyl acrylate, methyl
methacrylate, ethyl methacrylate, and copolymers thereof, with each
other or with additional acrylate species such as aminoethyl
acrylate; maleic anhydride copolymers; polymaleic acid;
poly(acrylamides) such as polyacrylamide per se,
poly(methacrylamide), poly(dimethylacrylamide), and
poly(N-isopropyl-acrylamide); polyalkylene oxides; poly(olefinic
alcohol)s such as poly(vinyl alcohol); poly(N-vinyl lactams) such
as poly(vinyl pyrrolidone), poly(N-vinyl caprolactam), and
copolymers thereof; polyols such as glycerol, polyglycerol
(particularly highly branched polyglycerol), propylene glycol and
trimethylene glycol substituted with one or more polyalkylene
oxides, e.g., mono-, di- and tri-polyoxyethylated glycerol, mono-
and di-polyoxyethylated propylene glycol, and mono- and
di-polyoxyethylated trimethylene glycol; polyoxyethylated sorbitol
and polyoxyethylated glucose; polyoxazolines, including
poly(methyloxazoline) and poly(ethyloxazoline); polyvinylamines;
polyvinylacetates, including polyvinylacetate per se as well as
ethylene-vinyl acetate copolymers, polyvinyl acetate phthalate, and
the like, polyimines, such as polyethyleneimine; starch and
starch-based polymers; polyurethane hydrogels; chitosan;
polysaccharide gums; xanthan gum; zein; and shellac, ammoniated
shellac, shellac-acetyl alcohol, and shellac n-butyl stearate. The
polymers may be used individually or in combination. Certain
combinations will often provide a more controlled release of
opioid(s), such as oxycodone, and API(s), such as acetaminophen,
than their components when used individually. Suitable combinations
include cellulose-based polymers combined with gums, such as
hydroxyethyl cellulose or hydroxypropyl cellulose combined with
xanthan gum, and poly(ethylene oxide) combined with xanthan
gum.
[0236] In one embodiment, the extended release polymer(s) may be a
cellulosic polymer, such as an alkyl substituted cellulose
derivative as detailed above. In terms of their viscosities, one
class of exemplary alkyl substituted celluloses includes those
whose viscosity is within the range of about 100 to about 110,000
centipoise as a 2% aqueous solution at 20.degree. C. Another class
includes those whose viscosity is within the range of about 1,000
to about 4,000 centipoise as a 1% aqueous solution at 20.degree.
C.
[0237] In one embodiment, the extended release polymer(s) may be a
polyalkylene oxide. In another aspect, the polyalkylene oxide may
be poly(ethylene) oxide. In a further embodiment, the
poly(ethylene) oxide may have an approximate molecular weight
between 500,000 Daltons (Da) to about 10,000,000 Da or about
900,000 Da to about 7,000,000 Da. In yet a further embodiment, the
poly(ethylene) oxide may have a molecular weight of approximately
about 600,000 Da, about 700,000 Da, about 800,000 Da, about 900,000
Da, about 1,000,000 Da, about 2,000,000 Da, about 3,000,000 Da,
about 4,000,000 Da, about 5,000,000 Da, about 6,000,000 Da, about
7,000,000 Da, about 8,000,000 Da, 9,000,000 Da, or 10,000,000
Da.
[0238] In another embodiment, the polyethylene oxide may be any
desirable grade of POLYOX.TM. or any combination thereof. By way of
example and without limitation, the POLYOX.TM. grade may be WSR
N-10, WSR N-80, WSR N-750, WSR 205, WSR 1105, WSR N-12K, WSR N-60K,
WSR-301, WSR Coagulant, WSR-303, WSR-308, WSR N-3000, UCARFLOC
Polymer 300, UCARFLOC Polymer 302, UCARFLOC Polymer 304, and
UCARFLOC Polymer 309. In one embodiment, the polyethylene oxide may
have an average molecular weight of from about 100,000 Da to about
8,000,000 Da. In another embodiment, the polyethylene oxide may
have an average molecular weight of about 100,000 Da, about 200,000
Da, about 300,000 Da, about 400,000 Da, about 500,000 Da, about
600,000 Da, about 700,000 Da, about 800,000 Da, about 900,000 Da,
about 1,000,000 Da, about 2,000,000 Da, about 3,000,000 Da, about
4,000,000 Da, about 5,000,000 Da, about 6,000,000 Da, about
7,000,000 Da, or about 8,000,000 Da. In still another embodiment,
the polyethylene oxide may have an average number of repeating
ethylene oxide units (--CH2CH2O--) of about 2,000 to about 160,000.
In yet another embodiment, the polyethylene oxide may have an
average number of repeating ethylene oxide units of about 2,275,
about 4,500, about 6,800, about 9,100, about 14,000, about 20,000,
about 23,000, about 45,000, about 90,000, about 114,000, or about
159,000.
[0239] The release profile of the extended release compositions
disclosed herein will depend partially upon the molecular weight of
the extended release polymer(s). In certain embodiments, the
polymers are of a moderate to high molecular weight (900,000 Da to
4,000,000 Da) to control release of the opioid, such as oxycodone
and/or the API(s), such as acetaminophen from the composition via
diffusion of the opioid(s) and/or other API out of the polymer
and/or erosion of the polymer. An example of suitable polyethylene
oxide polymers are those having molecular weights (viscosity
average) on the order of about 900,000 Da to about 2,000,000 Da.
Using a lower molecular weight ("MW") polyethylene oxide, such as
POLYOX.RTM. 1105 (900,000 MW), the release rates for drugs are
higher. Using a higher molecular weight polyethylene oxide (such as
POLYOX.RTM. N-60K (2,000,000 MW) or POLYOX.RTM. WSR-301 (4,000,000
MW) reduces the rate of release for drugs. In another embodiment of
the invention, a hydroxypropylmethylcellulose polymer of such
molecular weight is utilized so that the viscosity of a 2% aqueous
solution is about 4000 cps to greater than about 100,000 cps.
[0240] The release profile of the extended release pharmaceutical
composition disclosed herein may also depend upon the amount of the
extended release polymer(s) in the pharmaceutical composition. In
general, the release rates for all active agents may be decreased
by increasing the amount of the extended release polymer(s) in the
pharmaceutical composition. Stated another way, the release rates
for the opioid, such as oxycodone, and/or the additional API, such
as acetaminophen, may be slowed by increasing the amount of the
extended release polymer(s) in the pharmaceutical composition. By
way of example and without limitation, the release profile of all
active agents (e.g., acetaminophen and oxycodone) may be decreased
by increasing the amount of POLYOX.RTM. 1105 from about 25% by
weight of the ER portion to about 35% by weight of the ER
portion.
[0241] The amount of extended release polymer or polymers present
in the extended release portion(s) of the pharmaceutical
composition can and will vary. In one embodiment, the polymer
present in an extended release portion of the composition may range
from about 15% to about 70% (w/w), or about 20% to about 60% (w/w),
or about 25% to about 55% (w/w) of the total weight of such
extended release portion of the composition. In another embodiment,
the amount of polymer present in an extended release portion of the
pharmaceutical composition may range from about 30% to about 50%
(w/w) of the total weight of such extended release portion. In
still another embodiment, the amount of polymer present in an
extended release portion of the pharmaceutical composition may
range from about 35% to about 45% (w/w) of the total weight of such
extended release portion. In yet another embodiment, the amount of
polymer present in an extended release portion of the
pharmaceutical composition may be about 30%, 35%, 40%, 45%, 50%,
55%, or 60% (w/w) of the total weight of such extended release
portion. In one embodiment, the amount of polymer present in an
extended release portion of the pharmaceutical composition may be
about 35% (w/w) of the total weight of such extended release
portion. In another embodiment, the amount of polymer present in an
extended release portion of the pharmaceutical composition may be
about 45% (w/w) of the total weight of such extended release
portion. In one embodiment, the ER layer swells upon imbibition of
fluid to a size which is about 15%, 20%, 25%, 30%, 35% 40%, 45%,
50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% larger
than the size of the ER layer prior to imbibition of fluid. In
another embodiment, the ER layer swells upon imbibition of fluid to
a size at least about 25% larger than the size of the ER layer
prior to imbibition of fluid within about 15 minutes of the start
of fluid imbibition. In still another embodiment, the ER layer
swells upon imbibition of fluid to a size at least about 100%
larger than the size of the ER layer prior to imbibition of fluid
within about 45 min, 50 min, 60 min, 75 min, or 90 min of the start
of fluid imbibitions.
[0242] (iv) Excipients
[0243] The extended release portion(s) of the pharmaceutical
composition may further comprise at least one excipient. Suitable
excipients include binders, fillers, lubricants, antioxidants,
chelating agents, and color agents.
[0244] In one embodiment, the extended release portion(s) of the
pharmaceutical composition may comprise at least one binder.
Suitable binders include, without limit, starches (including corn
starch and pregelatinized starch), gelatin, sugars (including
sucrose, glucose, dextrose and lactose), polyethylene glycol,
polyols, polyvinylalcohols, C12-C18 fatty acid alcohols, waxes,
gums (e.g., guar gum, arabic gum, acacia gum, xanthan gum, etc.),
gelatin, pectin, sodium alginate, polyvinylpyrrolidone, cellulosic
polymers (including hydroxypropyl cellulose, hydroxypropyl
methylcellulose, hydroxylcellulose, methylcellulose,
microcrystalline cellulose, ethylcellulose, hydroxyethyl cellulose,
and the like), polyacrylamides, and polyvinyloxoazolidone. In one
embodiment, the amount of binder or binders in an extended release
portion of the pharmaceutical composition may range from about 0.5%
to about 8.0% (w/w) of such extended release portion. In various
embodiments, an extended release portion of the pharmaceutical
composition may comprise at least one binder that is present in an
amount that is about 0.5%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%,
1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%,
5.5%, or 6.0%, 6.5%, 7.0%, 7.5%, or 8.0% (w/w) of such extended
release portion of the composition.
[0245] In another embodiment, the at least one extended release
portion(s) of the pharmaceutical composition may comprise at least
one filler. Suitable fillers include but are not limited to
microcrystalline cellulose (MCC), dibasic calcium phosphate,
tribasic calcium phosphate, magnesium carbonate, magnesium oxide,
calcium silicate, magnesium aluminum silicate, silicon dioxide,
titanium dioxide, alumina, talc, kaolin, polyvinylpyrrolidone,
dibasic calcium sulfate, tribasic calcium sulfate, starch, calcium
carbonate, magnesium carbonate, carbohydrates, modified starches,
lactose, sucrose, dextrose, mannitol, sorbitol, and inorganic
compounds. In one embodiment, the amount of filler or fillers in an
extended release portion may range from about 2% to about 50% (w/w)
of the total weight of such extended release portion. In various
embodiments, an extended release portion of the pharmaceutical
composition may comprise at least one filler that is present in an
amount that is about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%,
13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%,
26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%,
39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50% (w/w)
of such extended release portion of the composition.
[0246] In a further embodiment, the extended release portion(s) of
the pharmaceutical composition may further comprise a lubricant.
Useful lubricants include magnesium stearate, calcium stearate,
stearic acid, and hydrogenated vegetable oil (preferably comprised
of hydrogenated and refined triglycerides of stearic and palmitic
acids). The lubricant may be present in an amount ranging from
about 0.1% to about 3.0% (w/w) of the total weight of the extended
release portion. In certain embodiments, the amount of lubricant in
an extended release portion may be about 0.25%, 0.5%, 0.75%, 1.0%,
1.5%, 1.75%, 1.80%, 1.85%, 1.90%, or 2.0% (w/w) of the total weight
of such extended release portion of the composition.
[0247] In yet another embodiment, the extended release portion(s)
of the pharmaceutical composition may comprise at least one
antioxidant. Suitable antioxidants include, without limit, ascorbic
acid, citric acid, ascorbyl palmitate, butylated hydroxyanisole, a
mixture of 2 and 3 tertiary-butyl-4-hydroxyanisole, butylated
hydroxytoluene, sodium isoascorbate, dihydroguaretic acid,
potassium sorbate, sodium bisulfate, sodium metabisulfate, sorbic
acid, potassium ascorbate, vitamin E,
4-chloro-2,6-ditertiarybutylphenol, alphatocopherol, and
propylgallate. The amount of antioxidant present in an extended
release portion of the pharmaceutical composition may range from
about 0.01% to about 4.0% (w/w), or from about 0.02% to about 0.10%
(w/w). In various embodiments, the amount of antioxidant present in
an extended release portion of the pharmaceutical composition may
be about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%,
0.09%, 0.10%, 0.12%, 0.14%, 0.16%, 0.18%. 0.20%, 0.25%, 0.50%,
0.75%, 1.00%, 1.50%, or 2.00% (w/w) of the total weight of such
extended release portion.
[0248] In still another embodiment, the extended release portion(s)
of the pharmaceutical composition may comprise at least one
chelating agent. Suitable chelating agents include ethylenediamine
tetracetic acid (EDTA) and its salts,
N-(hydroxy-ethyl)ethylenediaminetriacetic acid, nitrilotriacetic
acid (NIA), ethylene-bis(oxyethylene-nitrilo)tetraacetic acid,
1,4,7,10-tetraazacyclodo-decane-N,N',N'',N'''-tetraacetic acid,
1,4,7,10-tetraaza-cyclododecane-N,N',N''-triacetic acid,
1,4,7-tris(carboxymethyl)-10-(2'-hydroxypropyl)-1,4,7,10-tetraazocyclodec-
ane, 1,4,7-triazacyclonane-N,N',N''-triacetic acid,
1,4,8,11-tetraazacyclotetra-decane-N,N',N'',N'''-tetraacetic acid;
diethylenetriamine-pentaacetic acid (DTPA), ethylenedicysteine,
bis(aminoethanethiol)carboxylic acid,
triethylenetetraamine-hexaacetic acid, and
1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid. In one
embodiment, the chelating agent may be the sodium salt of EDTA. The
amount of chelating agent present in an extended release portion of
the pharmaceutical composition may range from about 0.001% to about
0.20% (w/w) of such extended release portion. In some embodiments,
the amount of chelating agent present in an extended release
portion of the pharmaceutical composition may be about 0.001%,
0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%,
0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%,
0.10%, 0.11%, 0.12%, 0.13%, 0.14%, or 0.15% (w/w) of the total
weight of such extended release portion.
[0249] In an alternate embodiment, the extended release portion(s)
of the pharmaceutical composition may comprise a color agent.
Suitable color additives include, but are not limited to, food,
drug and cosmetic colors (FD&C), drug and cosmetic colors
(D&C), and external drug and cosmetic colors (Ext. D&C). In
various embodiments, the amount of color agent present in an
extended release portion may range from about 2.0% to about 5.0%
(w/w) of such extended release portion of the composition. In other
embodiments, the amount of color agent present in an extended
release portion may be about 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%,
4.0%, 4.5%, or 5.0% (w/w) of such extended release portion.
(d) Dosage Forms of the Pharmaceutical Composition
[0250] (i) Physical Properties
[0251] The physical form of the pharmaceutical composition
disclosed herein can and will vary. In general, the pharmaceutical
composition is a solid dosage form comprising at least one extended
release portion and, optionally, at least one immediate release
portion. Suitable solid dosage forms include tablets, caplets,
capsules, encapsulated beads, and gelcaps. Non-limiting types of
tablets include coated tablets, uncoated tablets, bilayer tablets,
multiparticle tablets, monolithic tablets, matrix tablets,
compressed tablets, and molded tablets. Non-limiting types of
capsules include hard capsules and multi-layer capsules.
[0252] In one embodiment, the dosage form may be a capsule.
Non-limiting examples of suitable hard capsules include hard starch
capsules, hard gelatin capsules, hard cellulose capsules, and
hydrogel capsules. In one example, the core of the capsule may
comprise the at least one extended release portion and the shell of
the capsule may comprise the at least one immediate release portion
of the composition. In another example, the core of the capsule may
comprises one extended release portion, comprising oxycodone,
acetaminophen and an extended release component, and the shell of
the capsule may comprise one immediate release portion of the
composition comprising oxycodone and acetaminophen. In yet another
example, the core of the capsule may comprise two extended release
portions, each comprising an extended release component and one of
oxycodone or acetaminophen, and the shell of the capsule may
comprise two immediate release portions of the composition, each
comprising one of the oxycodone and the acetaminophen. In still
another embodiment, the dosage form may be a sustained release
capsule comprising the oxycodone or the acetaminophen and
exhibiting immediate release and/or extended release properties. In
yet another embodiment, the dosage form may be a delayed release
capsule comprising the oxycodone and/or acetaminophen and
exhibiting immediate release and/or extended release properties.
The capsule may comprise a coating. In one embodiment, the capsule
may comprise an enteric coating.
[0253] In another embodiment, the dosage form may be a tablet
comprising at least one extended release portion and at least one
immediate release portion. The at least one immediate release
portion may be adjacent to, abutting, or surrounding the at least
one extended release portion. In one embodiment, the dosage form
may be a bilayer tablet comprising one extended release layer
comprising the oxycodone and the acetaminophen and one immediate
release layer comprising the oxycodone and the acetaminophen. The
bilayer tablet may comprise a coating. In another embodiment, the
dosage form may be a multilayer tablet comprising two extended
release portions, each comprising one of the oxycodone and the
acetaminophen, and one immediate release portion comprising both
the oxycodone and the acetaminophen. In yet another embodiment, the
dosage form may be a multilayer tablet comprising two extended
release portions, each comprising one of the oxycodone and the
acetaminophen, and two immediate release portions, each comprising
one of the oxycodone and the acetaminophen. In still another
embodiment, the dosage form may be a sustained release tablet
comprising the oxycodone and/or acetaminophen and exhibiting
immediate release and/or extended release properties. In yet
another embodiment, the dosage form may be a delayed release tablet
comprising the oxycodone and/or acetaminophen and exhibiting
immediate release and/or extended release properties. The bilayer
tablet may comprise a coating. In one embodiment, the bilayer
tablet may comprise an enteric coating.
[0254] In certain embodiments, the tablet may have a friability of
no greater than about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.7% or 1.0%.
In another embodiment, the tablet may have a friability of greater
than 0 but less that about 1.0%, greater than 0 but less than about
0.5%, greater than 0 but less than about 0.3%, or greater than 0
but less than about 0.2%. In still another embodiment, the tablet
may have a friability of zero.
[0255] In another embodiment, the tablet may have a hardness of at
least about 10 Kilopond (also known as kilopons) (kp). In some
embodiments, the tablet may have a hardness of about 9 kp to about
25 kp, or about 12 kp to about 20 kp. In further embodiments, the
tablet may have a hardness of about 11 kp, 12 kp, 13 kp, 14 kp, 15
kp, 16 kp, 17 kp, 18 kp, 19 kp, or 20 kp.
[0256] In additional embodiments, the tablet may have a content
uniformity of from about 85 to about 115 percent by weight or from
about 90 to about 110 percent by weight, or from about 95 to about
105 percent by weight. In other embodiments, the content uniformity
may have a relative standard deviation (RSD) equal to or less than
about 3.5%, 3.0%, 2.5%, 2.0%, 1.5%, 1.0%, or 0.5%.
[0257] The pharmaceutical composition disclosed herein includes one
or more dosage forms that are designed to achieve the therapeutic
concentrations of the active ingredients. In some embodiments,
therefore, a therapeutically effective dose of the pharmaceutical
composition may comprise one dosage form. In other embodiments, a
therapeutically effective dose of the pharmaceutical composition
may comprise two dosage forms. In additional embodiments, a
therapeutically effective dose of the pharmaceutical composition
may comprise three or more dosage forms.
[0258] In still other embodiments, prior to administration to a
patient or immersion in fluid, the pharmaceutical composition may
have (i) a length of approximately 18 mm, 18.01 mm, 18.02 mm, 18.03
mm, 18.04 mm, 18.05 mm, 18.06 mm, 18.07 mm, 18.08 mm, 18.09 mm,
18.1 mm, 18.11 mm, 18.12 mm, 18.13 mm, 18.14 mm, 18.15 mm, 18.16
mm, 18.17 mm, 18.18 mm, 18.19 mm, 18.2 mm, 18.21 mm, 18.22 mm,
18.23 mm, 18.24 mm, 18.25 mm, 18.26 mm, 18.27 mm, 18.28 mm, 18.29
mm, 18.3 mm, 18.31 mm, 18.32 mm, 18.33 mm, 18.34 mm, 18.35 mm,
18.36 mm, 18.37 mm, 18.38 mm, 18.39 mm, 18.4 mm, 18.41 mm, 18.42
mm, 18.43 mm, 18.44 mm, 18.45 mm, 18.46 mm, 18.47 mm, 18.48 mm,
18.49 mm, 18.5 mm, 18.51 mm, 18.52 mm, 18.53 mm, 18.54 mm, 18.55
mm, 18.56 mm, 18.57 mm, 18.58 mm, 18.59 mm, 18.6 mm, 18.61 mm,
18.62 mm, 18.63 mm, 18.64 mm, 18.65 mm, 18.66 mm, 18.67 mm, 18.68
mm, 18.69 mm, 18.7 mm, 18.71 mm, 18.72 mm, 18.73 mm, 18.74 mm,
18.75 mm, 18.76 mm, 18.77 mm, 18.78 mm, 18.79 mm, 18.8 mm, 18.81
mm, 18.82 mm, 18.83 mm, 18.84 mm, 18.85 mm, 18.86 mm, 18.87 mm,
18.88 mm, 18.89 mm, 18.9 mm, 18.91 mm, 18.92 mm, 18.93 mm, 18.94
mm, 18.95 mm, 18.96 mm, 18.97 mm, 18.98 mm, 18.99 mm, 19 mm, 19.01
mm, 19.02 mm, 19.03 mm, 19.04 mm, 19.05 mm, 19.06 mm, 19.07 mm,
19.08 mm, 19.09 mm, 19.1 mm, 19.11 mm, 19.12 mm, 19.13 mm, 19.14
mm, 19.15 mm, 19.16 mm, 19.17 mm, 19.18 mm, 19.19 mm, 19.2 mm,
19.21 mm, 19.22 mm, 19.23 mm, 19.24 mm, 19.25 mm, 19.26 mm, 19.27
mm, 19.28 mm, 19.29 mm, 19.3 mm, 19.31 mm, 19.32 mm, 19.33 mm,
19.34 mm, 19.35 mm, 19.36 mm, 19.37 mm, 19.38 mm, 19.39 mm, 19.4
mm, 19.41 mm, 19.42 mm, 19.43 mm, 19.44 mm, 19.45 mm, 19.46 mm,
19.47 mm, 19.48 mm, 19.49 mm, 19.5 mm, 19.51 mm, 19.52 mm, 19.53
mm, 19.54 mm, 19.55 mm, 19.56 mm, 19.57 mm, 19.58 mm, 19.59 mm 19.6
mm, 19.61 mm, 19.62 mm, 19.63 mm, 19.64 mm, 19.65 mm, 19.66 mm,
19.67 mm, 19.68 mm, 19.69 mm, 19.7 mm, 19.71 mm, 19.72 mm, 19.73
mm, 19.74 mm, 19.75 mm, 19.76 mm, 19.77 mm, 19.78 mm, 19.79 mm,
19.8 mm, 19.81 mm, 19.82 mm, 19.83 mm, 19.84 mm, 19.85 mm, 19.86
mm, 19.87 mm, 19.88 mm, 19.89 mm, 19.9 mm, 19.91 mm, 19.92 mm,
19.93 mm, 19.94 mm, 19.95 mm, 19.96 mm, 19.97 mm, 19.98 mm, 19.99
mm, or 20 mm as measured on the major axis, (ii) a width of
approximately 11 mm, 11.01 mm, 11.02 mm, 11.03 mm, 11.04 mm, 11.05
mm, 11.06 mm, 11.07 mm, 11.08 mm, 11.09 mm, 11.1 mm, 11.11 mm,
11.12 mm, 11.13 mm, 11.14 mm, 11.15 mm, 11.16 mm, 11.17 mm, 11.18
mm, 11.19 mm, 11.2 mm, 11.21 mm, 11.22 mm, 11.23 mm, 11.24 mm,
11.25 mm, 11.26 mm, 11.27 mm, 11.28 mm, 11.29 mm, 11.3 mm, 11.31
mm, 11.32 mm, 11.33 mm, 11.34 mm, 11.35 mm, 11.36 mm, 11.37 mm,
11.38 mm, 11.39 mm, 11.4 mm, 11.41 mm, 11.42 mm, 11.43 mm, 11.44
mm, 11.45 mm, 11.46 mm, 11.47 mm, 11.48 mm, 11.49 mm, 11.5 mm,
11.51 mm, 11.52 mm, 11.53 mm, 11.54 mm, 11.55 mm, 11.56 mm, 11.57
mm, 11.58 mm, 11.59 mm, 11.6 mm, 11.61 mm, 11.62 mm, 11.63 mm,
11.64 mm, 11.65 mm, 11.66 mm, 11.67 mm, 11.68 mm, 11.69 mm, 11.7
mm, 11.71 mm, 11.72 mm, 11.73 mm, 11.74 mm, 11.75 mm, 11.76 mm,
11.77 mm, 11.78 mm, 11.79 mm, 11.8 mm, 11.81 mm, 11.82 mm, 11.83
mm, 11.84 mm, 11.85 mm, 11.86 mm, 11.87 mm, 11.88 mm, 11.89 mm,
11.9 mm, 11.91 mm, 11.92 mm, 11.93 mm, 11.94 mm, 11.95 mm, 11.96
mm, 11.97 mm, 11.98 mm, 11.99 mm, 12 mm, 12.01 mm, 12.02 mm, 12.03
mm, 12.04 mm, 12.05 mm, 12.06 mm, 12.07 mm, 12.08 mm, 12.09 mm,
12.1 mm, 12.11 mm, 12.12 mm, 12.13 mm, 12.14 mm, 12.15 mm, 12.16
mm, 12.17 mm, 12.18 mm, 12.19 mm, 12.2 mm, 12.21 mm, 12.22 mm,
12.23 mm, 12.24 mm, 12.25 mm, 12.26 mm, 12.27 mm, 12.28 mm, 12.29
mm, 12.3 mm, 12.31 mm, 12.32 mm, 12.33 mm, 12.34 mm, 12.35 mm,
12.36 mm, 12.37 mm, 12.38 mm, 12.39 mm, 12.4 mm, 12.41 mm, 12.42
mm, 12.43 mm, 12.44 mm, 12.45 mm, 12.46 mm, 12.47 mm, 12.48 mm,
12.49 mm, 12.5 mm, 12.51 mm, 12.52 mm, 12.53 mm, 12.54 mm, 12.55
mm, 12.56 mm, 12.57 mm, 12.58 mm, 12.59 mm, 12.6 mm, 12.61 mm,
12.62 mm, 12.63 mm, 12.64 mm, 12.65 mm, 12.66 mm, 12.67 mm, 12.68
mm, 12.69 mm, 12.7 mm, 12.71 mm, 12.72 mm, 12.73 mm, 12.74 mm,
12.75 mm, 12.76 mm, 12.77 mm, 12.78 mm, 12.79 mm, 12.8 mm, 12.81
mm, 12.82 mm, 12.83 mm, 12.84 mm, 12.85 mm, 12.86 mm, 12.87 mm,
12.88 mm, 12.89 mm, 12.9 mm, 12.91 mm, 12.92 mm, 12.93 mm, 12.94
mm, 12.95 mm, 12.96 mm, 12.97 mm, 12.98 mm, 12.99 mm, or 13 mm, and
(iii) a height or thickness of approximately 5 mm, 5.01 mm, 5.02
mm, 5.03 mm, 5.04 mm, 5.05 mm, 5.06 mm, 5.07 mm, 5.08 mm, 5.09 mm,
5.1 mm, 5.11 mm, 5.12 mm, 5.13 mm, 5.14 mm, 5.15 mm, 5.16 mm, 5.17
mm, 5.18 mm, 5.19 mm, 5.2 mm, 5.21 mm, 5.22 mm, 5.23 mm, 5.24 mm,
5.25 mm, 5.26 mm, 5.27 mm, 5.28 mm, 5.29 mm, 5.3 mm, 5.31 mm, 5.32
mm, 5.33 mm, 5.34 mm, 5.35 mm, 5.36 mm, 5.37 mm, 5.38 mm, 5.39 mm,
5.4 mm, 5.41 mm, 5.42 mm, 5.43 mm, 5.44 mm, 5.45 mm, 5.46 mm, 5.47
mm, 5.48 mm, 5.49 mm, 5.5 mm, 5.51 mm, 5.52 mm, 5.53 mm, 5.54 mm,
5.55 mm, 5.56 mm, 5.57 mm, 5.58 mm, 5.59 mm, 5.6 mm, 5.61 mm, 5.62
mm, 5.63 mm, 5.64 mm, 5.65 mm, 5.66 mm, 5.67 mm, 5.68 mm, 5.69 mm,
5.7 mm, 5.71 mm, 5.72 mm, 5.73 mm, 5.74 mm, 5.75 mm, 5.76 mm, 5.77
mm, 5.78 mm, 5.79 mm, 5.8 mm, 5.81 mm, 5.82 mm, 5.83 mm, 5.84 mm,
5.85 mm, 5.86 mm, 5.87 mm, 5.88 mm, 5.89 mm, 5.9 mm, 5.91 mm, 5.92
mm, 5.93 mm, 5.94 mm, 5.95 mm, 5.96 mm, 5.97 mm, 5.98 mm, 5.99 mm,
or 6 mm. In yet another embodiment, the pharmaceutical composition
may have (i) a length of approximately 19.1 mm, 19.11 mm, 19.12 mm,
19.13 mm, 19.14 mm, 19.15 mm, 19.16 mm, 19.17 mm, 19.18 mm, 19.19
mm, 19.2 mm, 19.21 mm, 19.22 mm, 19.23 mm, 19.24 mm, 19.25 mm,
19.26 mm, 19.27 mm, 19.28 mm, 19.29 mm, or 19.3 mm as measured on
the major axis, (ii) a width of approximately 12.4 mm, 12.41 mm,
12.42 mm, 12.43 mm, 12.44 mm, 12.45 mm, 12.46 mm, 12.47 mm, 12.48
mm, 12.49 mm, or 12.5 mm, and (iii) a height or thickness of
approximately 5.6 mm, 5.61 mm, 5.62 mm, 5.63 mm, 5.64 mm, 5.65 mm,
5.66 mm, 5.67 mm, 5.68 mm, 5.69 mm, 5.7 mm, 5.71 mm, 5.72 mm, 5.73
mm, 5.74 mm, 5.75 mm, 5.76 mm, 5.77 mm, 5.78 mm, 5.79 mm, or 5.8
mm.
[0259] In additional embodiments, the pharmaceutical composition
may expand upon immersion in fluid to have (i) a length of about
18.5 mm, 18.6 mm, 18.7 mm, 18.8 mm, 18.9 mm, 19 mm, 19.1 mm, 19.2
mm, 19.3 mm, 19.4 mm, 19.5 mm, 19.6 mm, 19.7 mm, 19.8 mm, 19.9 mm,
20 mm, 20.1 mm, 20.2 mm, 20.3 mm, 20.4 mm, 20.5 mm, 20.6 mm, 20.7
mm, 20.8 mm, 20.9 mm, or 21 mm; and (ii) a width of about 11 mm,
11.1 mm, 11.2 mm, 11.3 mm, 11.4 mm, 11.5 mm, 11.6 mm, 11.7 mm, 11.8
mm, 11.9 mm, 12 mm, 12.1 mm, 12.2 mm, 12.3 mm, 12.4 mm, 12.5 mm,
12.6 mm, 12.7 mm, 12.8 mm, 12.9 mm, 13 mm, 13.1 mm, 13.2 mm, 13.3
mm, 13.4 mm, 13.5 mm, 13.6 mm, 13.7 mm, 13.8 mm, 13.9 mm, or 14 mm
within about 5 minutes of immersion in fluid. In other embodiments,
the pharmaceutical composition may expand upon immersion in fluid
to (i) a length of about 18.5 mm, 18.6 mm, 18.7 mm, 18.8 mm, 18.9
mm, 19 mm, 19.1 mm, 19.2 mm, 19.3 mm, 19.4 mm, 19.5 mm, 19.6 mm,
19.7 mm, 19.8 mm, 19.9 mm, 20 mm, 20.1 mm, 20.2 mm, 20.3 mm, 20.4
mm, 20.5 mm, 20.6 mm, 20.7 mm, 20.8 mm, 20.9 mm, 21 mm, 21.1 mm,
21.2 mm, 21.3 mm, 21.4 mm, 21.5 mm, 21.6 mm, 21.7 mm, 21.8 mm, 21.9
mm, or 22 mm; and (ii) a width of about 11 mm, 11.1 mm, 11.2 mm,
11.3 mm, 11.4 mm, 11.5 mm, 11.6 mm, 11.7 mm, 11.8 mm, 11.9 mm, 12
mm, 12.1 mm, 12.2 mm, 12.3 mm, 12.4 mm, 12.5 mm, 12.6 mm, 12.7 mm,
12.8 mm, 12.9 mm, 13 mm, 13.1 mm, 13.2 mm, 13.3 mm, 13.4 mm, 13.5
mm, 13.6 mm, 13.7 mm, 13.8 mm, 13.9 mm, 14 mm, 14.1 mm, 14.2 mm,
14.3 mm, 14.4 mm, 14.5 mm, 14.6 mm, 14.7 mm, 14.8 mm, 14.9 mm, or
15 mm within about 10 minutes to about 15 minutes of immersion in
fluid. In still other embodiments, the pharmaceutical composition
may expand upon immersion in fluid to (i) a length of about 19 mm,
19.1 mm, 19.2 mm, 19.3 mm, 19.4 mm, 19.5 mm, 19.6 mm, 19.7 mm, 19.8
mm, 19.9 mm, 20 mm, 20.1 mm, 20.2 mm, 20.3 mm, 20.4 mm, 20.5 mm,
20.6 mm, 20.7 mm, 20.8 mm, 20.9 mm, 21 mm, 21.1 mm, 21.2 mm, 21.3
mm, 21.4 mm, 21.5 mm, 21.6 mm, 21.7 mm, 21.8 mm, 21.9 mm, 22 mm,
22.1 mm, 22.2 mm, 22.3 mm, 22.4 mm, or 22.5 mm; and (ii) a width of
about 12 mm, 12.1 mm, 12.2 mm, 12.3 mm, 12.4 mm, 12.5 mm, 12.6 mm,
12.7 mm, 12.8 mm, 12.9 mm, 13 mm, 13.1 mm, 13.2 mm, 13.3 mm, 13.4
mm, 13.5 mm, 13.6 mm, 13.7 mm, 13.8 mm, 13.9 mm, 14 mm, 14.1 mm,
14.2 mm, 14.3 mm, 14.4 mm, 14.5 mm, 14.6 mm, 14.7 mm, 14.8 mm, 14.9
mm, or 15 mm within about 20 minutes to about 25 minutes of
immersion in fluid. In additional embodiments, the pharmaceutical
composition may expand upon immersion in fluid to (i) a length of
about 19 mm, 19.1 mm, 19.2 mm, 19.3 mm, 19.4 mm, 19.5 mm, 19.6 mm,
19.7 mm, 19.8 mm, 19.9 mm, 20 mm, 20.1 mm, 20.2 mm, 20.3 mm, 20.4
mm, 20.5 mm, 20.6 mm, 20.7 mm, 20.8 mm, 20.9 mm, 21 mm, 21.1 mm,
21.2 mm, 21.3 mm, 21.4 mm, 21.5 mm, 21.6 mm, 21.7 mm, 21.8 mm, 21.9
mm, 22 mm, 22.1 mm, 22.2 mm, 22.3 mm, 22.4 mm, 22.5 mm, 22.6 mm,
22.7 mm, 22.8 mm, 22.9 mm, or 23 mm; and (ii) a width of about 12.5
mm, 12.6 mm, 12.7 mm, 12.8 mm, 12.9 mm, 13 mm, 13.1 mm, 13.2 mm,
13.3 mm, 13.4 mm, 13.5 mm, 13.6 mm, 13.7 mm, 13.8 mm, 13.9 mm, 14
mm, 14.1 mm, 14.2 mm, 14.3 mm, 14.4 mm, 14.5 mm, 14.6 mm, 14.7 mm,
14.8 mm, 14.9 mm, or 15 mm within about 30 minutes to about 35
minutes of immersion in fluid. In still other embodiments, the
pharmaceutical composition may expand upon immersion in fluid to
(i) a length of about 18 mm, 18.1 mm, 18.2 mm, 18.3 mm, 18.4 mm,
18.5 mm, 18.6 mm, 18.7 mm, 18.8 mm, 18.9 mm, 19 mm, 19.1 mm, 19.2
mm, 19.3 mm, 19.4 mm, 19.5 mm, 19.6 mm, 19.7 mm, 19.8 mm, 19.9 mm,
20 mm, 20.1 mm, 20.2 mm, 20.3 mm, 20.4 mm, 20.5 mm, 20.6 mm, 20.7
mm, 20.8 mm, 20.9 mm, 21 mm, 21.1 mm, 21.2 mm, 21.3 mm, 21.4 mm,
21.5 mm, 21.6 mm, 21.7 mm, 21.8 mm, 21.9 mm, 22 mm, 22.1 mm, 22.2
mm, 22.3 mm, 22.4 mm, 22.5 mm, 22.6 mm, 22.7 mm, 22.8 mm, 22.9 mm,
23 mm, 23.1 mm, 23.2 mm, 23.3 mm, 23.4 mm, or 23.5; (ii) a width of
about 11.5 mm, 11.6 mm, 11.7 mm, 11.8 mm, 11.9 mm, 12 mm, 12.1 mm,
12.2 mm, 12.3 mm, 12.4 mm, 12.5 mm, 12.6 mm, 12.7 mm, 12.8 mm, 12.9
mm, 13 mm, 13.1 mm, 13.2 mm, 13.3 mm, 13.4 mm, 13.5 mm, 13.6 mm,
13.7 mm, 13.8 mm, 13.9 mm, 14 mm, 14.1 mm, 14.2 mm, 14.3 mm, 14.4
mm, 14.5 mm, 14.6 mm, 14.7 mm, 14.8 mm, 14.9 mm, 15 mm, 15.1 mm,
15.2 mm, 15.3 mm, 15.4 mm, 15.5 mm, 15.6 mm, 15.7 mm, 15.8 mm, 15.9
mm, or 16 mm; and (iii) a height or thickness of about 5.5 mm, 5.6
mm, 5.7 mm, 5.8 mm, 5.9 mm, 6 mm, 6.1 mm, 6.2 mm, 6.3 mm, 6.4 mm,
6.5 mm, 6.6 mm, 6.7 mm, 6.8 mm, 6.9 mm, or 7 mm within about 50
minutes to about 55 minutes of immersion in fluid. In yet another
embodiment, the pharmaceutical composition may expand upon
immersion in fluid to (i) a length of about 19.5 mm, 19.6 mm, 19.7
mm, 19.8 mm, 19.9 mm, 20 mm, 20.1 mm, 20.2 mm, 20.3 mm, 20.4 mm,
20.5 mm, 20.6 mm, 20.7 mm, 20.8 mm, 20.9 mm, 21 mm, 21.1 mm, 21.2
mm, 21.3 mm, 21.4 mm, 21.5 mm, 21.6 mm, 21.7 mm, 21.8 mm, 21.9 mm,
22 mm, 22.1 mm, 22.2 mm, 22.3 mm, 22.4 mm, 22.5 mm, 22.6 mm, 22.7
mm, 22.8 mm, 22.9 mm, 23 mm, 23.1 mm, 23.2 mm, 23.3 mm, 23.4 mm, or
23.5; (ii) a width of about 13 mm, 13.1 mm, 13.2 mm, 13.3 mm, 13.4
mm, 13.5 mm, 13.6 mm, 13.7 mm, 13.8 mm, 13.9 mm, 14 mm, 14.1 mm,
14.2 mm, 14.3 mm, 14.4 mm, 14.5 mm, 14.6 mm, 14.7 mm, 14.8 mm, 14.9
mm, 15 mm, 15.1 mm, 15.2 mm, 15.3 mm, 15.4 mm, 15.5 mm, 15.6 mm,
15.7 mm, 15.8 mm, 15.9 mm, or 16 mm; and (iii) a height or
thickness of about 5.5 mm, 5.6 mm, 5.7 mm, 5.8 mm, 5.9 mm, 6 mm,
6.1 mm, 6.2 mm, 6.3 mm, 6.4 mm, 6.5 mm, 6.6 mm, 6.7 mm, 6.8 mm, 6.9
mm, or 7 mm within about 60 minutes of immersion in fluid.
[0260] In yet another embodiment, the length of the pharmaceutical
composition increases by about 4%, 4.25%, 4.5% 4.75%, 5%, 5.25%,
5.5%, 5.75%, 6%, 6.25%, 6.5%, 6.75%, 7%, 7.25%, 7.5%, 7.75%, 8%,
8.25%, 8.5%, 8.75%, 9%, 9.25%, 9.5%, 9.75%, 10%, 10.25%, 10.5%,
10.75%, 11%, 11.25%, 11.5%, 11.75%, 12%, 12.25%, 12.5%, 12.75%, or
13% within about 10 minutes of immersion in fluid. In still another
embodiment, the length of the pharmaceutical composition increases
by about 5%, 5.25%, 5.5%, 5.75%, 6%, 6.25%, 6.5%, 6.75%, 7%, 7.25%,
7.5%, 7.75%, 8%, 8.25%, 8.5%, 8.75%, 9%, 9.25%, 9.5%, 9.75%, 10%,
10.25%, 10.5%, 10.75%, 11%, 11.25%, 11.5%, 11.75%, 12%, 12.25%,
12.5%, 12.75%, 13%, 13.25%, 13.5%, 13.75%, 14%, 14.25%, 14.5%,
14.75%, or 15% within about 15 minutes of immersion in fluid. In
yet another embodiment, the length of the pharmaceutical
composition increases by about 5%, 5.25%, 5.5%, 5.75%, 6%, 6.25%,
6.5%, 6.75%, 7%, 7.25%, 7.5%, 7.75%, 8%, 8.25%, 8.5%, 8.75%, 9%,
9.25%, 9.5%, 9.75%, 10%, 10.25%, 10.5%, 10.75%, 11%, 11.25%, 11.5%,
11.75%, 12%, 12.25%, 12.5%, 12.75%, 13%, 13.25%, 13.5%, 13.75%,
14%, 14.25%, 14.5%, 14.75%, or 15% within about 20 minutes of
immersion in fluid. In a further embodiment, the length of the
pharmaceutical composition increases by about 7%, 7.25%, 7.5%,
7.75%, 8%, 8.25%, 8.5%, 8.75%, 9%, 9.25%, 9.5%, 9.75%, 10%, 10.25%,
10.5%, 10.75%, 11%, 11.25%, 11.5%, 11.75%, 12%, 12.25%, 12.5%,
12.75%, 13%, 13.25%, 13.5%, 13.75%, 14%, 14.25%, 14.5%, 14.75%,
15%, 15.25%, 15.5%, 15.75%, 16%, 16.25%, 16.5%, 16.75%, 17%,
17.25%, 17.5%, 17.75%, or 18% within about 30 minutes of immersion
in fluid. In another embodiment, the length of the pharmaceutical
composition increases by about 8%, 8.25%, 8.5%, 8.75%, 9%, 9.25%,
9.5%, 9.75%, 10%, 10.25%, 10.5%, 10.75%, 11%, 11.25%, 11.5%,
11.75%, 12%, 12.25%, 12.5%, 12.75%, 13%, 13.25%, 13.5%, 13.75%,
14%, 14.25%, 14.5%, 14.75%, 15%, 15.25%, 15.5%, 15.75%, 16%,
16.25%, 16.5%, 16.75%, 17%, 17.25%, 17.5%, 17.75%, 18%, 18.25%,
18.5%, 18.75%, or 19% within about 45 minutes of immersion in
fluid. In yet another embodiment, the length of the pharmaceutical
composition increases by about 8%, 8.25%, 8.5%, 8.75%, 9%, 9.25%
9.5%, 9.75%, 10%, 10.25%, 10.5%, 10.75%, 11%, 11.25%, 11.5%,
11.75%, 12%, 12.25%, 12.5%, 12.75%, 13%, 13.25%, 13.5%, 13.75%,
14%, 14.25%, 14.5%, 14.75%, 15%, 15.25%, 15.5%, 15.75%, 16%,
16.25%, 16.5%, 16.75%, 17%, 17.25%, 17.5%, 17.75%, 18%, 18.25%,
18.5%, 18.75%, or 19% within about 55 minutes of immersion in
fluid. In still another embodiment, the length of the
pharmaceutical composition increases by about 8%, 8.25%, 8.5%,
8.75%, 9%, 9.25%, 9.5%, 9.75%, 10%, 10.25%, 10.5%, 10.75%, 11%,
11.25%, 11.5%, 11.75%, 12%, 12.25%, 12.5%, 12.75%, 13%, 13.25%,
13.5%, 13.75%, 14%, 14.25%, 14.5%, 14.75%, 15%, 15.25%, 15.5%,
15.75%, 16%, 16.25%, 16.5%, 16.75%, 17%, 17.25%, 17.5%, 17.75%,
18%, 18.25%, 18.5%, 18.75%, 19%, 19.25%, 19.5%, 19.75%, or 20%
within about 60 minutes of immersion in fluid.
[0261] In a further embodiment, the width of the pharmaceutical
composition increases by about 6%, 6.25%, 6.5%, 6.75%, 7%, 7.25%,
7.5%, 7.75%, 8%, 8.25%, 8.5%, 8.75%, 9%, 9.25%, 9.5%, 9.75%, 10%,
10.25%, 10.5%, 10.75%, 11%, 11.25%, 11.5%, 11.75%, 12%, 12.25%,
12.5%, 12.75%, 13%, 13.25%, 13.5%, 13.75%, 14%, 14.25%, 14.5%,
14.75%, or 15% within about 10 minutes of immersion in fluid. In
still another embodiment, the width of the pharmaceutical
composition increases by about 6%, 6.25%, 6.5%, 6.75%, 7%, 7.25%,
7.5%, 7.75%, 8%, 8.25%, 8.5%, 8.75%, 9%, 9.25%, 9.5%, 9.75%, 10%,
10.25%, 10.5%, 10.75%, 11%, 11.25%, 11.5%, 11.75%, 12%, 12.25%,
12.5%, 12.75%, 13%, 13.25%, 13.5%, 13.75%, 14%, 14.25%, 14.5%,
14.75%, 15%, 15.25%, 15.5%, 15.75%, 16%, 16.25%, 16.5%, 16.75%,
17%, 17.25%, 17.5%, 17.75%, or 18%, within about 15 minutes of
immersion in fluid. In yet another embodiment, the width of the
pharmaceutical composition increases by about 6%, 6.25%, 6.5%,
6.75%, 7%, 7.25%, 7.5%, 7.75%, 8%, 8.25%, 8.5%, 8.75%, 9%, 9.25%,
9.5%, 9.75%, 10%, 10.25%, 10.5%, 10.75%, 11%, 11.25%, 11.5%,
11.75%, 12%, 12.25%, 12.5%, 12.75%, 13%, 13.25%, 13.5%, 13.75%,
14%, 14.25%, 14.5%, 14.75%, 15%, 15.25%, 15.5%, 15.75%, 16%,
16.25%, 16.5%, 16.75%, 17%, 17.25%, 17.5%, 17.75%, or 18%, within
about 20 minutes of immersion in fluid. In a further embodiment,
the width of the pharmaceutical composition increases by about 10%,
10.25%, 10.5%, 10.75%, 11%, 11.25%, 11.5%, 11.75%, 12%, 12.25%,
12.5%, 12.75%, 13%, 13.25%, 13.5%, 13.75%, 14%, 14.25%, 14.5%,
14.75%, 15%, 15.25%, 15.5%, 15.75%, 16%, 16.25%, 16.5%, 16.75%,
17%, 17.25%, 17.5%, 17.75%, 18%, 18.25%, 18.5%, 18.75%, 19%,
19.25%, 19.5%, 19.75%, 20%, 20.25%, 20.5%, 20.75%, 21%, 21.25%,
21.5%, 21.75%, 22%, 22.25%, 22.5%, 22.75%, 23%, 23.25%, 23.5%,
23.75%, or 24% within about 30 minutes of immersion in fluid. In
another embodiment, the width of the pharmaceutical composition
increases by about 12%, 12.25%, 12.5%, 12.75%, 13%, 13.25%, 13.5%,
13.75%, 14%, 14.25%, 14.5%, 14.75%, 15%, 15.25%, 15.5%, 15.75%,
16%, 16.25%, 16.5%, 16.75%, 17%, 17.25%, 17.5%, 17.75%, 18%,
18.25%, 18.5%, 18.75%, 19%, 19.25%, 19.5%, 19.75%, 20%, 20.25%,
20.5%, 20.75%, 21%, 21.25%, 21.5%, 21.75%, 22%, 22.25%, 22.5%,
22.75%, 23%, 23.25%, 23.5%, 23.75%, 24%, 24.25%, 24.5%, 24.75%, or
25% within about 45 minutes of immersion in fluid. In yet another
embodiment, the width of the pharmaceutical composition increases
by about 12%, 12.25%, 12.5%, 12.75%, 13%, 13.25%, 13.5%, 13.75%,
14%, 14.25%, 14.5%, 14.75%, 15%, 15.25%, 15.5%, 15.75%, 16%,
16.25%, 16.5%, 16.75%, 17%, 17.25%, 17.5%, 17.75%, 18%, 18.25%,
18.5%, 18.75%, 19%, 19.25%, 19.5%, 19.75%, 20.25%, 20.5%, 20.75%,
21%, 21.25%, 21.5%, 21.75%, 22%, 22.25%, 22.5%, 22.75%, 23%,
23.25%, 23.5%, 23.75%, 24%, 24.25%, 24.5%, 24.75%, or 25% within
about 55 minutes of immersion in fluid. In still another
embodiment, the width of the pharmaceutical composition increases
by about 14%, 14.25%, 14.5%, 14.75%, 15%, 15.25%, 15.5%, 15.75%,
16%, 16.25%, 16.5%, 16.75%, 17%, 17.25%, 17.5%, 17.75%, 18%,
18.25%, 18.5%, 18.75%, 19%, 19.25%, 19.5%, 19.75%, 20%, 20.25%,
20.5%, 20.75%, 21%, 21.25%, 21.5%, 21.75%, 22%, 22.25%, 22.5%,
22.75%, 23%, 23.25%, 23.5%, 23.75%, 24%, 24.25%, 24.5%, 24.75%,
25%, 25.25%, 25.5%, 25.75%, or 26% within about 60 minutes of
immersion in fluid.
[0262] In some embodiments, the composition disclosed herein may
have gastric retentive properties. These gastric retentive
properties of the composition may be due to a combination of a
physical property of the composition and/or the release of the
opioid. In one embodiment, the gastric retentive properties of the
opioid-containing extended release composition is provided by the
use of a polymer. In one embodiment, the opioid-containing extended
release composition comprises a gastric retentive polymer in an
amount of about 1% to about 99%. In another embodiment, the
opioid-containing extended release composition comprises a gastric
retentive polymer in an amount of about 10% to about 80%. In yet
another embodiment, the opioid-containing extended release
composition comprises a gastric retentive polymer in an amount of
about 20% to about 60%. In other embodiments, the opioid-containing
extended release composition comprises a gastric retentive polymer
in an amount of about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%,
12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%,
25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%,
38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%,
51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%,
64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%,
77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%,
90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.
[0263] In another embodiment, the composition may be expandable.
That is, the composition has size that is small enough for oral
intake, but the composition absorbs water from the gastric fluid
and swells to a size that prevents its passage through the pylorus.
Such a composition comprises at least one swellable, expandable
material, such as a polymer, resin, hydrocolloid, hydrogel, or the
like. In various embodiments, the composition may swell to a size
that is about 110% to about 200% of the original volume within
about 30 minutes of administration. For example, the composition
may swell to approximately 115% of it original volume within 30
minutes of administration, and at a later time may swell to a
volume that is 130% or more of the original volume. In other
embodiments, the composition may exhibit a volume increase of
two-fold or more. Additionally, the composition may become slippery
upon absorption of water, which provides resistance to peristalsis
and further promotes gastric retention. The swellable material
degrades or erodes over a specified period of time (e.g., the
dosing interval) such that the composition is no longer retained in
the stomach. In one embodiment, the ER layer swells upon imbibition
of fluid to a size which is about 15%, 20%, 25%, 30%, 35% 40%, 45%,
50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% larger
than the size of the ER layer prior to imbibition of fluid. In
another embodiment, the ER layer swells upon imbibition of fluid to
a size at least about 25% larger than the size of the ER layer
prior to imbibition of fluid within about 15 minutes of the start
of fluid imbibition. In still another embodiment, the ER layer
swells upon imbibition of fluid to a size at least about 100%
larger than the size of the ER layer prior to imbibition of fluid
within about 45 min, 50 min, 60 min, 75 min, or 90 min of the start
of fluid imbibitions.
[0264] In a further embodiment, the composition contains at least
one swellable polymer. For example, the composition may include
chitosan, methylcellulose, polyvinyl acetate, purified shellac,
polyethylene oxide, polypropylene oxide, or an expansive polymeric
film, such as one composed of polyvinyl acetate and shellac. In
another embodiment, the composition may contain a combination of
polymers in a matrix that is swellable. Exemplary swellable
matrices are described in U.S. Pat. Nos. 6,723,340, 6,340,475, and
6,635,280, the disclosures of which are herein incorporated by
reference in their entirety.
[0265] In still another embodiment, the physical property of the
composition that imparts gastric retention may be the shape of the
composition. For example, the composition may have a ring,
tetrahedron, spiral, coil, planar disc, planar multilobe,
continuous stick, sheet, oval, parallelogram, or string geometric
configuration, wherein the composition is unable to pass through
the pyloric sphincter. In some iterations, the composition may be
folded into a pharmaceutical carrier (e.g., a gelatin capsule) or
secured by readily dissolvable (e.g., gelatin) strips such that,
upon dissolution of the carrier or strips, the composition unfolds
in the stomach. In general, unfoldable compositions comprise
biodegradable polymers such that the composition is degraded and/or
reduced in size over a specified period of time (e.g., the dosing
interval). In another embodiment, the composition has a diameter of
greater than or equal to 7.5 mm. Exemplary shaped dosage forms are
described in U.S. Pat. No. 6,488,962, the entirety of which is
herein incorporated by reference.
[0266] In yet another embodiment, the physical property of the
composition that imparts gastric retention may be the adhesivity of
the composition. Bio-mucoadhesive compositions bind to the gastric
epithelial cell surface, or mucin, and increase gastric retention
time by increasing the intimacy and duration of contact between the
composition and the biological membrane. Bio-mucoadhesive
compositions generally comprise polycarbophil, carbopol,
cholestyramine, chitosan, polymeric acids, or a natural or
synthetic polymer that is capable of adhering to a biological
membrane (e.g., a bioadhesive polymer) or the mucus lining of the
stomach or intestinal tract (e.g., a mucoadhesive polymer).
Exemplary adhesive polymers include anionic (e.g.,
carboxymethylcellulose, chondroitin sulfate, polyacrylic acid,
pectin, carageenan, chitosan, and alginic acid), cationic (e.g.,
polylysine and polybrene), and neutral (e.g., polyethylene glycol,
polyvinyl pyrrolidone, and dextran) polymers. Certain hydrophilic
polymers tend to imbibe large amounts of water and become sticky,
thereby acquiring bioadhesive properties. The adhesion of polymers
to a mucus or epithelial cell surface may involve various bonding
mechanisms, including physical-mechanical bonding and chemical
bonding. Physical-mechanical bonding may result from the insertion
of the adhesive material into the crevices or folds of the mucosa.
Chemical bonds may be either covalent or non-covalent (e.g., ionic
bonds, hydrogen bonds, van der Waals interactions, etc). Moreover,
certain polymers may bind to specific receptor sites on the surface
of cells, thereby enhancing the gastric retention. For example,
certain plant lectins interact specifically with the sugar groups
present in mucus or on the glycocalyx.
[0267] In still another embodiment, the physical property of the
composition that imparts gastric retention may be the density of
the composition. In one iteration, the composition may have a low
density with sufficient buoyancy such that the composition floats
over the gastric contents and remains in the stomach for a
prolonged period. Floating compositions may be effervescent or
noneffervescent. Effervescent compositions generally comprise
matrices prepared with swellable polymers and an effervescent
component. For example, the effervescent component can be either a
carbonate or bicarbonate salt (e.g., sodium bicarbonate, calcium
bicarbonate), an organic acid (e.g., citric acid, tartaric acid),
or any combination thereof. The effervescent component can also be
a floating chamber filled with vacuum, air, an inert gas, or a
liquid that gasifies at body temperature. Floatability is generally
achieved by generation of gas bubbles. Gas may be introduced into
the floating chamber by the volatilization of an organic solvent,
or by an effervescent reaction between a carbonate-bicarbonate salt
and an organic acid. The matrices may be fabricated so that upon
arrival in the stomach, carbon dioxide is liberated by the acidity
of the gastric contents and is entrapped in the gellified matrix.
This maintains the buoyancy of the composition, causing it to
float. In another embodiment, the composition may also contain a
polymer which exhibits floating characteristics, such as
hydroxypropyl cellulose, hydroxypropyl methylcellulose,
crospovidone, sodium carboxymethyl cellulose, or ethyl cellulose.
In a further embodiment, the composition may comprise a device
having a hollow deformable unit that converts from a collapsed to
expanded form and vise versa. The unit is supported by a housing
that is internally divided into two chambers separated by a
pressure-sensitive movable bladder. The first chamber contains the
therapeutic agent and the second contains a volatile liquid (e.g.,
cyclopentane, ether) that vaporizes at body temperature and imparts
buoyancy to the system. The system also contains a bioerodible plug
to aid in the exit from the body. Further embodiments of this two
chamber system are disclosed in U.S. Pat. Nos. 3,901,232 and
3,786,813, which are hereby incorporated by reference. In still a
further embodiment, the composition may contain hollow microspheres
or microballoons, which cause the composition to float. The
composition may also comprise floating microparticles such as
polypropylene foam, Eudragit, ethyl cellulose, or polymethyl metha
acylate (PMMA).
[0268] Noneffervescent compositions incorporate a high level of one
or more gel-forming, highly swellable, cellulosic hydrocolloids.
Upon contact with the gastric contents, these hydrocolloids hydrate
and forms a colloidal gel barrier, wherein air trapped by the
swollen hydrocolloid confers buoyancy to this composition. In
another iteration, the composition may have a density that exceeds
the density of normal gastric contents such the composition sinks
to the bottom of the stomach (i.e., the antrum) where it is
entrapped in the folds of the antrum and withstands the peristaltic
waves of the gastric wall. In yet another iteration, the
composition has a density that is greater than or equal to 1.3
g/mL.
[0269] In one embodiment, the composition is retained in the
stomach due to the presence of an extended release polymer that
absorbs water from the gastric contents and swells or expands to a
size that cannot pass through the pyloric sphincter. As a
consequence, the opioid and the other API are slowly released from
the composition in the stomach and absorbed in the upper
gastrointestinal tract.
[0270] In still another embodiment, the physical property of the
composition that results in gastric retention may be the physical
size of the composition. That is, the composition may have a size
that is small enough to be orally ingested and enter the stomach,
but large enough to prevent passage through the pyloric sphincter
into the small intestine. In some embodiments in which the
composition is designed for humans, the composition may have a
length (or diameter) of more than about 7 mm, 8 mm, 9 mm, or 10 mm.
In other embodiments in which the composition is designed for
humans, the composition may have a length (or diameter) of more
than about 11 mm, 12 mm, or 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18
mm, 19 mm, 20 mm or longer. In still other embodiments, the
composition may have (i) a length of approximately 19 mm, 19.1 mm,
19.2 mm, 19.3 mm, 19.4 mm, 19.5 mm, 19.6 mm, 19.7 mm, 19.8 mm, 19.9
mm, or 20 mm as measured on the major axis, (ii) a width of
approximately 12 mm, 12.1 mm, 12.2 mm, 12.3 mm, 12.4 mm, 12.5 mm,
12.6 mm, 12.7 mm, 12.8 mm, 12.9 mm, or 13 mm as measured on the
minor axis, and (iii) a height or thickness of approximately 5 mm,
5.1 mm, 5.2 mm, 5.3 mm, 5.4 mm, 5.5 mm, 5.6 mm, 5.7 mm, 5.8 mm, 5.9
mm, or 6 mm. In yet another embodiment, the composition may have
(i) a length of approximately 19.1 mm, 19.11 mm, 19.12 mm, 19.13
mm, 19.14 mm, 19.15 mm, 19.16 mm, 19.17 mm, 19.18 mm, 19.19 mm,
19.2 mm, 19.21 mm, 19.22 mm, 19.23 mm, 19.24 mm, 19.25 mm, 19.26
mm, 19.27 mm, 19.28 mm, 19.29 mm, or 19.3 mm as measured on the
major axis, (ii) a width of approximately 12.4 mm, 12.41 mm, 12.42
mm, 12.43 mm, 12.44 mm, 12.45 mm, 12.46 mm, 12.47 mm, 12.48 mm,
12.49 mm, or 12.5 mm as measured on the minor axis, and (iii) a
height or thickness of approximately 5.6 mm, 5.61 mm, 5.62 mm, 5.63
mm, 5.64 mm, 5.65 mm, 5.66 mm, 5.67 mm, 5.68 mm, 5.69 mm, 5.7 mm,
5.71 mm, 5.72 mm, 5.73 mm, 5.74 mm, 5.75 mm, 5.76 mm, 5.77 mm, 5.78
mm, 5.79 mm, or 5.8 mm. In general, such compositions are designed
to degrade, disintegrate, decrease in size, or collapse in a
specified time interval (e.g., dosing interval) such that they may
pass through the pyloric valve or be evacuated from the stomach by
a housekeeper wave of gastric contractions.
[0271] In still another embodiment, the composition may contain an
agent which delays the passage of the composition through the
pyloric sphincter. For example, the composition may include
triethanol amine myristate or propantheline.
[0272] (ii) Opioid Release
[0273] Because opioids, such as oxycodone, reduce gastric motility,
the erosion time of the dosage form can be increased (thus,
hindering drug release) if the opioid is not properly dosed. The
gastric retentive extended release composition disclosed herein is
engineered to release the opioid(s) at a rate that is sufficient to
delay gastric emptying such that the composition is retained in the
stomach for a longer period of time than a comparable composition
that is not gastric retentive. For example, the composition may be
designed to release the opioid(s) at a rate that delays gastric
emptying by about 15 minutes, 30 minutes, 60 minutes, 90 minutes,
2.0 hours, 2.5 hours, 3.0 hours, 3.5 hours, 4.0 hours, 4.5 hours,
or 5.0 hours. The rate of release of the opioid(s) may be
manipulated by selecting a suitable extended release component for
inclusion in an extended release portion of the composition. For
example, in embodiments in which the extended release component is
an extended release polymer, the extended release polymer generally
is selected such that the composition releases the opioid(s) at a
rate that delays gastric emptying by the desired amount.
Additionally, the rate of release of the opioid(s) from the
composition may be adjusted by selecting the proper ratio of opioid
present in the at least one immediate release and the at least one
extended release portions of the composition. For instance, the
proportion of the opioid(s) in the at least one immediate release
portion and the at least one extended release portion may be about
20:80, 21:79, 22:78, 23:77; 24:76, 25:75, 26:74, 27:73, 28;72,
29:71, 30:70, 31:69, 32:68, 33:67, 34:66, 35:65, 34:66, 35:65,
36:64, 37:63, 38:62, 39:61, or 40:60.
[0274] Additionally, the gastric retentive extended release
composition is engineered to release the opioid(s) at a rate that
is insufficient to cause any serious adverse gastrointestinal
effects. Adverse gastrointestinal effects include, but are not
limited to, intestinal hypomotility, intestinal blockage,
intestinal pseudo-obstruction, abdominal distention, bloating,
constipation, intestinal distress, severe intestinal contractions,
colon spasms, hypoactive bowel, and increased anal sphincter
tone.
[0275] (iii) Overall Composition
[0276] With the knowledge of the preferred dissolution and
pharmacokinetic profiles for the opioid and the additional API, and
the pharmacodynamics effects of the opioid and the additional API,
as discovered by the applicants and first described herein, a
composition exhibiting the same or similar dissolution and
pharmacokinetic profiles and pharmacodynamics effects can be
developed using any of the dosage forms discussed above. Moreover,
a composition under the present invention can be developed using
another dosage form that achieves the same or similar dissolution,
pharmacokinetic, and pharmacodynamic profiles as the compositions
disclosed herein. For example, in one embodiment, a
controlled=release dosage form can be developed that exhibits
pharmacokinetic and pharmacodynamic parameters (e.g., Cmax, AUC)
which are within 80% to 125% at a confidence interval of 90% of
those parameters for the compositions described herein. In another
embodiment, a sustained release dosage form can be developed that
exhibits pharmacokinetic and pharmacodynamic parameters which are
within 80% to 125% at a confidence interval of 90% of those
parameters for the compositions described herein. A composition
could also be developed that lacks one of the specific gastric
retentive dosage forms discussed above, yet, achieves the same
dissolution and pharmacokinetic profiles, and exhibits the
pharmacodynamic effects.
[0277] For example, a gastric retentive extended release
composition as described herein may comprise an opioid, such as
oxycodone, an additional API, such as acetaminophen, an immediate
release portion, and a gastric retentive portion, wherein the
immediate release and gastric retentive portions comprise a filler
and a lubricant. In one embodiment, the immediate release and
gastric retentive portions may each comprise a filler in an amount
of about 5 mg to about 500 mg. In another embodiment, the immediate
release and gastric retentive portions may each comprise a filler
in an amount of about 20 mg to about 400 mg. In yet another
embodiment, the immediate release and gastric retentive portions
may each comprise a filler in an amount of about 40 mg to about 300
mg.
[0278] In one embodiment, the immediate release and gastric
retentive portions may each comprise a lubricant in an amount of
about 0.1 mg to about 25 mg. In another embodiment, the immediate
release and gastric retentive portions may each comprise a
lubricant in an amount of about 0.4 mg to about 15 mg. In still
another embodiment, the immediate release and gastric retentive
portions may each comprise a lubricant in an amount of about 0.7 mg
to about 5 mg. In another aspect, the gastric retentive portion may
further comprise between about 0 mg to about 50 mg of an
effervescent agent, such as a bicarbonate salt.
[0279] As discussed above, an extended release composition without
gastric retention is also described herein. In one embodiment, an
extended release composition as described herein may comprise an
opioid, such as oxycodone, an additional API, such as
acetaminophen, an immediate release portion, and an extended
release portion, wherein the immediate release and extended release
portions comprise a filler in an amount of about 5 mg to about 500
mg and a lubricant in an amount of about 0.1 mg to about 25 mg. The
extended release portion may comprise any suitable extended release
polymer. In one embodiment, the extended release polymer is present
in an amount of about 5 mg to about 500 mg. In another embodiment,
the extended release polymer is present in an amount of about 20 mg
to about 400 mg. In a further embodiment, the extended release
polymer is present in an amount of about 40 mg to about 300 mg
[0280] For example, some exemplary formulations of the gastric
retentive (Examples A-I) or sustained release (Examples J-R) dosage
forms described above are as follows:
TABLE-US-00001 CHART A Exemplary Gastric Retentive and Sustained
Release Dosage Forms. A B C Immediate Release Oxycodone HCl
Oxycodone HCl Oxycodone HCl Portion (0-15 mg) (0-7.5 mg) (0-15 mg)
APAP (0-325 mg) APAP (0-175 mg) APAP (200-325 mg) Filler (5-100 mg)
Filler (5-250 mg) Filler (50-75 mg) Lubricant (0.1-5 mg) Stearate
salt (0.1-10 Lubricant (2-3 mg) mg) Gastric Retentive Oxycodone HCl
Oxycodone HCL Oxycodone HCl Portion (0-15 mg) (0-7.5 mg) (0-15 mg)
APAP (0-325 mg) APAP (0-175 mg) APAP (100-325 mg) Polymer (5-500
mg) Polymer (50-750 Polymer (100-250 Filler (5-100 mg) mg) mg)
Lubricant (0.1-5 mg) Filler (5-250 mg) Filler (25-50 mg) Stearate
Salt Lubricant (1-3 mg) (0.1-10 mg) Immediate Release Oxycodone HCl
Oxycodone HCl Oxycodone HCl (2-5 Portion (5-10 mg) (5-10 mg) mg)
APAP (100-400 mg) APAP (100-400 mg) APAP (300-450 mg) Filler (25-50
mg) Filler (25-50 mg) Filler (25-75 mg) Lubricant (3-5 mg)
Lubricant (3-5 mg) Lubricant (2-5 mg) Gastric Retentive Oxycodone
HCl Oxycodone HCl Oxycodone HCl Portion (5-10 mg) (5-10 mg) (3-10
mg) APAP (50-250 mg) APAP (50-250 mg) APAP (50-300 mg) Filler
(50-75 mg) Filler (50-75 mg) Filler (50-75 mg) Polycarbophil
Polymer (5-500 mg) Polymer (100-450 mg) (5-500 mg) Bicarbonate salt
Bicarbonate salt Lubricant (3-5 mg) (0-10 mg) (0-10 mg) Lubricant
(3-5 mg) Lubricant (3-5 mg) Immediate Release Oxycodone HCl
Oxycodone HCl Oxycodone HCl Portion (1-10 mg) (0-15 mg) (0-15 mg)
APAP (100-325 mg) APAP (0-325 mg) APAP (0-325 mg) Filler (25-75 mg)
Filler (5-100 mg) Filler (5-100 mg) Lubricant (2-5 mg) Lubricant
(0.1-5 mg) Lubricant (0.1-5 mg) Gastric Retentive Oxycodone HCl
Oxycodone HCl Oxycodone HCl Portion (3-10 mg) (0-15 mg) (0-15 mg)
APAP (100-450 mg) APAP (0-325 mg) APAP (0-325 mg) Filler (5-100 mg)
Polyacrylate Cholestyramine Carbopol (5-500 (100-300 mg) (100-300
mg) mg) Filler (5-100 mg) Filler (5-100 mg) Lubricant (3-5 mg)
Immediate Release Oxycodone HCl Oxycodone HCl Oxycodone HCl Portion
(0-15 mg) (0-7.5 mg) (0-15 mg) APAP (0-325 mg) APAP (0-175 mg) APAP
(200-325 mg) Filler (5-100 mg) Filler (5-250 mg) Filler (50-75 mg)
Lubricant (0.1-5 mg) Stearate salt (0.1-10 mg) Lubricant (2-3 mg)
Extended Release Oxycodone HCl Oxycodone HCL Oxycodone HCl Portion
(0-15 mg) (0-7.5 mg) (0-15 mg) APAP (0-325 mg) APAP (0-175 mg) APAP
(100-325 mg) Polymer (5-500 mg) Polymer (50-750 Polymer (100-250
Filler (5-100 mg) mg) mg) Lubricant (0.1-5 mg) Filler (5-250 mg)
Filler (25-50 mg) Stearate Salt Lubricant (1-3 mg) (0.1-10 mg)
Immediate Release Oxycodone HCl Oxycodone HCl Oxycodone HCl (2-5
Portion (5-10 mg) (5-10 mg) mg) APAP (100-400 mg) APAP (100-400 mg)
APAP (300-450 mg) Filler (25-50 mg) Filler (25-50 mg) Filler (25-75
mg) Lubricant (3-5 mg) Lubricant (3-5 mg) Lubricant (2-5 mg)
Extended Release Oxycodone HCl Oxycodone HCl Oxycodone HCl Portion
(5-10 mg) (5-10 mg) (3-10 mg) APAP (50-250 mg) APAP (50-250 mg)
APAP (50-300 mg) Filler (50-75 mg) Filler (50-75 mg) Filler (50-75
mg) Methacrylate Hydroxy Propylmethyl copolymer (5-500 propylmethyl
cellulose (100-450 mg) cellulose (5-500 mg) mg) Lubricant (0.1-10
Lubricant (0.1-10 Lubricant (0.1-10 mg) mg) mg) Immediate Release
Oxycodone HCl Oxycodone HCl Oxycodone HCl Portion (1-10 mg) (0-15
mg) (0-15 mg) APAP (100-325 mg) APAP (0-325 mg) APAP (0-325 mg)
Filler (25-75 mg) Filler (5-100 mg) Filler (5-100 mg) Lubricant
(2-5 mg) Lubricant (0.1-5 mg) Lubricant (0.1-5 mg) Extended Release
Oxycodone HCl Oxycodone HCl Oxycodone HCl Portion (3-10 mg) (0-15
mg) (0-15 mg) APAP (100-450 mg) APAP (0-325 mg) APAP (0-325 mg)
Filler (5-100 mg) Ethylcellulose Polyacrylate (5-500 Alginate
(5-500 mg) (5-500 mg) mg) Lubricant (3-5 mg) Filler (5-100 mg)
Filler (5-100 mg) Sustained Release Oxycodone HCl Oxycodone HCl
Oxycodone HCl Formulation (1-15 mg) (1-15 mg) (1-15 mg) APAP
(50-650 mg) APAP (50-650 mg) APAP (50-650 mg) Filler (0-100 mg)
Filler (0-100 mg) Filler (0-100 mg) Methacrylate Hydroxy
Propylmethyl copolymer (5-500 propylmethyl cellulose (5-550 mg) mg)
cellulose (5-500 mg) Lubricant (0.1-10 Lubricant (0.1-10 Lubricant
(0.1-10 mg) mg) mg) Sustained Release Oxycodone HCl Oxycodone HCl
Oxycodone HCl Formulation (1-15 mg) (1-15 mg) (1-15 mg) APAP
(50-650 mg) APAP (50-650 mg) APAP (50-650 mg) Filler (0-100 mg)
Filler (0-100 mg) Filler (0-100 mg) Alginate (5-500 mg) Polysorbate
(5-500 Polyacrylate (5-550 Lubricant (0.1-10 mg) mg) mg) Lubricant
(0.1-10 Lubricant (0.1-10 mg) mg)
(e) Abuse and Tamper Resistant Properties of the Composition
[0281] Extended release pain medications have provided many
benefits to patients in the management of their chronic pain by
providing a sustained release over time of a larger quantity of
drug than is typically contained in an immediate release
formulation. Consequently, these dosage forms (especially if they
contain opioids) are attractive targets for drug abusers looking to
defeat the extended release formulation to allow immediate bolus
administration or "dose-dumping" of the entire drug contents of the
dosage form.
[0282] Dosage forms of the pharmaceutical composition disclosed
herein may be more resistant to crushing, grinding, pulverizing, or
other common means used to produce a powder than an immediate
release product. Accordingly, some embodiment forms are tamper
resistant and less prone to abuse or misuse. For example, certain
embodiments may not be crushed into a powder and snorted.
Additionally, some embodiments comprising an extended release
polymer may not be crushed, mixed with an aqueous solution, and
injected (i.e., the resultant mixture becomes extremely viscous and
cannot be effectively drawn into a syringe.)
[0283] For example, dosage forms of the pharmaceutical composition
disclosed herein form a pasty semi-solid mixture when dissolved.
Thus, the pharmaceutical composition is difficult to draw into a
syringe and inject intravenously. The yield of active
pharmaceutical ingredient(s) obtained from the pharmaceutical
composition is also low (less than 20%).
[0284] Further, dosage forms of the pharmaceutical composition
disclosed herein cannot easily be snorted. In order for a drug
abuser to successfully snort a drug obtained from a dosage form, he
must prepare a crushed, finely divided powder form of the dosage
form for insufflating the powder into the nasal cavity. However,
the pharmaceutical compositions disclosed herein form a clumpy,
solid mass upon insufflation and do not allow acceptable absorption
through the nasal tissue.
[0285] Dosage forms of the pharmaceutical composition disclosed
herein also do not allow "dose dumping" caused by the deliberate
introduction of alcohol into a drug abuser's stomach which
accelerates the release of active ingredient(s) from the
time-release formulation. The pharmaceutical compositions disclosed
herein are resistant to the accelerated release of active
ingredient(s).
[0286] In addition, dosage forms of the pharmaceutical composition
disclosed herein do not allow for "free basing." Successful free
basing by a drug abuser requires the generation of a salt free form
of the active pharmaceutical ingredient(s). This requires physical
and chemical manipulation to release the active pharmaceutical
ingredient(s) from its salt(s) and selective extraction from other
matrix excipients. The pharmaceutical composition disclosed herein
cannot be easily manipulated to generate a free base
preparation.
[0287] Moreover, the tamper resistance properties of the
pharmaceutical compositions disclosed herein may be increased by
increasing the average molecular weight of the extended release
polymer used in the pharmaceutical composition. In another
embodiment, the tamper resistance properties of the pharmaceutical
compositions disclosed herein may be increased by increasing the
amount of the extended release polymer used in the pharmaceutical
composition.
[0288] In further embodiments, the solid oral dosage forms of the
pharmaceutical compositions disclosed herein exhibit substantial
differences in the release profiles of oxycodone and acetaminophen
when the dosage forms are crushed or ground. Indeed, the intact
solid oral dosage forms surprisingly exhibit a higher release rate
of both active ingredients than one that is crushed or ground. This
suggests that upon grinding or crushing the solid oral dosage forms
disclosed herein, the immediate release portion and extended
release portion of the dosage form combine, and the hydration and
swelling of the polymer(s) in the extended release portion of the
dosage form retards the release of the oxycodone and acetaminophen
in the immediate release portion, and may also retard the release
of the oxycodone and acetaminophen in the extended release portion.
Hence the incorporation of the ground or crushed components from
the immediate release portion into a mixture with the ground or
crushed components of the extended release portion causes the
pharmaceutical composition to lose its immediate release
characteristics. This feature may effectively negate a drug
abuser's purpose for crushing the solid oral dosage form in the
first place--to obtain an early onset of analgesia. Indeed, when
the dosage forms disclosed herein are crushed or ground, the
absorption of oxycodone and acetaminophen is delayed, thereby
delaying the onset of euphoria as compared to when the dosage forms
are ingested in an intact state. Thus, this is an unexpected tamper
resistant property of the pharmaceutical compositions disclosed
herein.
[0289] It was also surprisingly discovered that when an extended
release dosage form disclosed herein (such as a bilayer tablet
comprising an immediate release layer and an extended release
layer), containing oxycodone and acetaminophen was administered to
a subject, all the AUC measurements for oxycodone and acetaminophen
were higher when the tablet was administered in an intact state
versus when the tablet was administered in a crushed or ground
state. For example, in one embodiment, the AUC measurements for
either oxycodone and/or acetaminophen were about 5% to about 60%
higher when a subject ingested the tablet in an intact state versus
a crushed or ground state. In another embodiment, the AUC
measurements for either oxycodone and/or acetaminophen were about
10% to about 50% higher when a subject ingested the tablet in an
intact state versus a crushed or ground. In yet another embodiment,
the AUC measurements for either oxycodone and/or acetaminophen were
about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%,
18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%
higher when a subject ingested the tablet in an intact state versus
in a crushed or ground state.
[0290] In a further embodiment, the AUC.sub.(0-1hr) for either
oxycodone and/or acetaminophen was about 50%, 100%, 150%, 200%,
250%, 300%, 350%, 400%, 450%, 500%, 550%, 600%, 650% 700%, 750%,
800%, 850%, 900%, 950%, or 1000% higher when a subject ingested the
tablet in an intact state versus in a crushed or ground state. In
another embodiment, the AUC.sub.(0-1hr) for either oxycodone and/or
acetaminophen will be about 50% to about 1000% higher when a
subject ingested the tablet in an intact state versus in a crushed
or ground state. In a further embodiment, the AUC.sub.(0-1hr) for
either oxycocodone and/or acetaminophen will be about 100% to about
900% higher when a subject ingested the tablet in an intact state
versus in a crushed or ground state. In still a further embodiment,
the AUC.sub.(0-1hr) for either oxycodone and/or acetaminophen will
be about 200% to about 800% higher when a subject ingested the
tablet in an intact state versus in a crushed or ground state. In
yet another embodiment, the AUC.sub.(0-1hr) for either oxycodone
and/or acetaminophen was about 300% to about 700% higher when a
subject ingested the tablet in an intact state versus in a crushed
or ground state.
[0291] In another embodiment, the AUC.sub.(0-2hr) for either
oxycodone and/or acetaminophen was about 50%, 100%, 150%, 200%,
250%, 300%, 350%, 400%, 450%, or 500% higher when a subject
ingested the tablet in an intact state versus in a crushed or
ground state. In another embodiment, the AUC.sub.(0-2hr) for either
oxycodone and/or acetaminophen will be about 50% to about 500%
higher when a subject ingested the tablet in an intact state versus
in a crushed or ground state. In a further embodiment, the
AUC.sub.(0-2hr) for either oxycodone and/or acetaminophen will be
about 100% to about 400% higher when a subject ingested the tablet
in an intact state versus in a crushed or ground state. In still a
further embodiment, the AUC.sub.(0-2hr) for either oxycodone and/or
acetaminophen will be about 150% to about 300% higher when a
subject ingested the tablet in an intact state versus in a crushed
or ground state. In an additional embodiment, the AUC.sub.(0-2hr)
for either oxycodone and/or acetaminophen was about 50% to about
250% higher when a subject ingested the tablet in an intact state
versus in a crushed or ground state.
[0292] In another embodiment, the AUC.sub.(0-4hr) for either
oxycodone and/or acetaminophen will be about 5%, 10%, 15%, 20%,
25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,
90%, 95%, or 100% higher when a subject ingested the tablet in an
intact state versus in a crushed or ground state. In a further
embodiment, the AUC.sub.(0-4hr) for either oxycodone and/or
acetaminophen will be about 25% to about 75% higher when a subject
ingested the tablet in an intact state versus in a crushed or
ground state. In still another embodiment, the AUC.sub.(0-8hr) for
either oxycodone and/or acetaminophen will be about 10%, 20%, 30%,
40%, 50%, 60%, 70% or 80% higher when a subject ingested the tablet
in an intact state versus in a crushed or ground state. In an
additional embodiment, the AUC.sub.(0-8hr) for either oxycodone
and/or acetaminophen will be about 10% to about 45% higher when a
subject ingested the tablet in an intact state versus in a crushed
or ground state.
[0293] In still another embodiment, the AUC.sub.(0-8hr) for either
oxycodone and/or acetaminophen was about 10%, 20%, 30%, 40%, 50%,
60%, 70% or 80% higher when a subject ingested the tablet in an
intact state versus in a crushed or ground state. In an additional
embodiment, the AUC.sub.(0-8hr) for either oxycodone and/or
acetaminophen was about 10% to about 45% higher when a subject
ingested the tablet in an intact state versus in a crushed or
ground state.
[0294] In another embodiment, the AUC.sub.(0-inf) for either
oxycodone and/or acetaminophen will be about 2%, 3%, 4%, 5%, 6%,
7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%,
21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%,
34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%,
47%, 48%, 49%, or 50% higher when a subject ingested the tablet in
an intact state versus in a crushed or ground state. In still
another embodiment, the AUC.sub.(0-inf) for either oxycodone and/or
acetaminophen will be from about 5% to about 40% higher when a
subject ingested the tablet in an intact state versus in a crushed
or ground state. In still another embodiment, the AUC.sub.(0-inf)
for either oxycodone and/or acetaminophen will be from about 7% to
about 30% higher when a subject ingested the tablet in an intact
state versus in a crushed or ground state. In a further embodiment,
the AUC.sub.(0-inf) for either oxycodone and/or acetaminophen will
be from about 10% to about 30% higher when a subject ingested the
tablet in an intact state versus in a crushed or ground state.
[0295] In another embodiment, the AUC.sub.(0-t) for either
oxycodone and/or acetaminophen will be about 2%, 3%, 4%, 5%, 6%,
7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%,
21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%,
34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%,
47%, 48%, 49%, or 50% higher when a subject ingested the tablet in
an intact state versus in a crushed or ground state. In another
embodiment, the AUC.sub.(0-t) for either oxycodone and/or
acetaminophen will be from about 2% to about 40% higher when a
subject ingested the tablet in an intact state versus in a crushed
or ground state. In still another embodiment, the AUC.sub.(0-t) for
either oxycodone and/or acetaminophen will be from about 3% to
about 30% higher when a subject ingested the tablet in an intact
state versus in a crushed or ground state. In a further embodiment,
the AUC.sub.(0-t) for either oxycodone and/or acetaminophen will be
from about 4% to about 30% higher when a subject ingested the
tablet in an intact state versus in a crushed or ground state. In
another embodiment, the AUC.sub.(0-t) for either oxycodone and/or
acetaminophen will be from about 5% to about 20% higher when a
subject ingested the tablet in an intact state versus in a crushed
or ground state.
[0296] Unexpectedly, the T.sub.max for both oxycodone and/or
acetaminophen was lower when the tablet was administered in an
intact state versus when the tablet was administered in a crushed
or ground state. For instance, in one embodiment, the T.sub.max for
either oxycodone and/or acetaminophen was lower by about 5% to
about 70% when the tablet was administered in an intact state
versus when the tablet was administered in a crushed or ground
state. In an additional embodiment, the T.sub.max for either
oxycodone and/or acetaminophen was lower by about 10% to about 40%
when the tablet was administered in an intact state versus when the
tablet was administered in a crushed or ground state. In another
embodiment, the T.sub.max for either hydrocodone and/or
acetaminophen will be about 20% to about 60%. In still another
embodiment, the T.sub.max for either oxycodone and/or acetaminophen
was about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%,
17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%,
30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%,
43%, 44%, 45%, 46%, 46%, 48%, 49% or 50% higher when a subject
ingested the tablet in a crushed or ground state versus in an
intact state. In yet another embodiment, the T.sub.max for either
oxycodone and/or acetaminophen was about 25%, 50%, 75%, 100%, 125%,
150%, 175%, 200%, 225%, 250%, 300% or 325% higher when a subject
ingested the tablet in a crushed or ground state versus in an
intact state. In an additional embodiment, administration of the
tablet to a subject produces a mean T.sub.max for either oxycodone
or acetaminophen that is at least about 30 minutes greater when the
tablet is administered in a crushed or ground state as compared to
an intact state. In a further embodiment, administration of the
tablet to a subject produces a mean T.sub.max for either oxycodone
or acetaminophen that is at least about 30 minutes, 45 minutes, 60
minutes, 75 minutes, 90 minutes, 105 minutes, 120 minutes, 135
minutes, or 150 minutes greater when the tablet is administered in
a crushed or ground state as compared to an intact state.
[0297] And the C.sub.max for acetaminophen was higher when the
tablet was administered in an intact state versus when the tablet
was administered in a crushed or ground state. For example, in one
embodiment, the Cmax for acetaminophen was about 5% to about 50%
higher when the tablet was administered in an intact state versus
when the tablet was administered in a crushed or ground state. In
yet another embodiment, the C.sub.max for acetaminophen was about
5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%,
19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%,
32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%,
45%, 46%, 46%, 48%, 49% or 50% higher when the tablet was
administered in an intact state versus when the tablet was
administered in a crushed or ground state.
[0298] In one embodiment, the abuse quotient of the tablet will be
higher when the tablet is administered in an intact state versus
when the tablet is administered in a crushed or ground state. For
example, in another embodiment, the abuse quotient may decrease in
an amount of from about 5% to about 90% when the tablet is
administered in a crushed or ground state versus in an intact
state. In a further embodiment, the abuse quotient may decrease in
an amount from about 10% to about 80% when the tablet is
administered in a crushed or ground state versus in an intact
state. In yet another embodiment, the abuse quotient may decrease
in an amount from about 15% to about 80% when the tablet is
administered in a crushed or ground state versus in an intact
state. In still another embodiment, the abuse quotient may decrease
in an amount of from about 20% to about 70% when the tablet is
administered in a crushed or ground state versus in an intact
state. In another embodiment, the abuse quotient may decrease in an
amount of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%,
55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% when the tablet is
administered in a crushed or ground state versus in an intact
state.
[0299] As a result of these pharmacokinetic parameters, a drug
abuser is more likely to take the extended release dosage forms
disclosed herein that comprise an immediate release portion and an
extended release portion in an intact form rather than in a crushed
form. Moreover, drug abusers "like" the dosage forms disclosed
herein better when the dosage forms are taken in an intact state
rather than in a crushed or ground state. See FDA's Guidance for
Industry Document titled, "Assessment of Abuse Potential of Drug,"
dated January 2010. Both overall and "at the moment" drug liking
may be assessed on a bipolar visual analog scale (VAS) anchored by
"strong disliking" (0), "neutral" (50), and "strong liking"
(100).
[0300] In another embodiment, as the amount of oxycodone in the
pharmaceutical composition increases, so does the duration of
gastric retention after administration to a subject. Consequently,
if a subject either intentionally or accidentally ingests a larger
dose of the pharmaceutical composition than prescribed, the
pharmaceutical composition will be retained in the stomach for a
longer time period than an IR or traditional ER pharmaceutical
composition, thereby giving a medical provider additional time to
perform gastric lavage, induce vomiting, or administer activated
charcoal to prevent the body from absorbing the oxycodone. In a
further embodiment, the pharmaceutical composition provides a
medical provider with about an additional 15 minutes, 30 minutes,
45 minutes, 60 minutes, 75 minutes, 90 minutes, 105 minutes, 2.0
hours, 2.25 hours, 2.5 hours, 2.75 hours, 3.0 hours, 3.25 hours,
3.5 hours, 3.75 hours, or 4 hours in which to prevent the
absorption of oxycodone in the subject. In another embodiment, the
pharmaceutical composition provides a medical provider with
sufficient time to treat a subject who has overdosed on oxycodone
so that death, difficulty breathing, cardiac arrest, and limp
muscles do not occur in the subject.
[0301] In yet another embodiment, if vomiting is induced or
naturally occurs as a result of an increased dose of oxycodone, the
entire pharmaceutical composition is expelled from the subject.
Thus, toxic concentrations of the oxycodone due to absorption into
the subject's blood are prevented by removing the further release
of oxycodone. In still another embodiment, if vomiting is induced
or naturally occurs as a result of the increased dose of oxycodone
about 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or
100% of the pharmaceutical composition is expelled from the
subject. In yet another embodiment, if vomiting is induced or
naturally occurs within about 30 minutes to about 60 minutes after
ingestion of the increased dose of oxycodone about 50% to about 65%
of the oxycodone dose is expelled from the subject.
(f) In Vitro Release Properties of the Composition
[0302] The in vitro release rates of oxycodone and acetaminophen
from the pharmaceutical compositions disclosed herein may be
measured in 900 mL of 0.1 N HCl using a USP type II paddle
apparatus and at a paddle speed of either about 100 rpm or 150 rpm
and a constant temperature of 37.degree. C.
[0303] In one embodiment, the at least one immediate release
portion of the composition may have in vitro release rates of
oxycodone and acetaminophen as follows: more than about 90% of the
oxycodone and/or the acetaminophen present in the at least one
immediate release portion may be released within about 15 minutes,
or essentially 100% of the oxycodone and/or the acetaminophen
present in the at least one immediate release portion may be
released within about 15 minutes. In another embodiment, more than
about 90% of the oxycodone and/or the acetaminophen present in the
at least one immediate release portion may be released within about
5 minutes. In yet another embodiment, essentially 100% of the
oxycodone and/or acetaminophen present in the at least one
immediate release portion may be released within about 5
minutes.
[0304] In one embodiment, the at least one extended release portion
of the composition may have in vitro release rates of oxycodone as
follows: from about 1% to about 20% of the oxycodone present in the
at least one extended release portion may be released within about
15 minutes, from about 35% to about 55% of the oxycodone present in
the at least one extended release portion may be released within
about 2 hours, from about 65% to about 85% of the oxycodone present
in the at least one extended release portion may be released within
about 4 hours, and at least about 90% of the oxycodone present in
the at least one extended release portion may be released within
about 8 hours.
[0305] In yet another embodiment, the at least one extended release
portion may have in vitro release rates of oxycodone as follows:
from about 1% to about 10% of the oxycodone present in the at least
one extended release portion may be released within about 15
minutes, from about 40% to about 50% of the oxycodone present in
the at least one extended release portion may be released within
about 2 hours, from about 70% to about 80% of the oxycodone present
in the at least one extended release portion may be released within
about 4 hours, and from about 90% to about 100% of the oxycodone
present in the at least one extended release portion may be
released within about 8 hours.
[0306] In one embodiment, the at least one extended release portion
may have in vitro release rates of acetaminophen as follows: from
about 1')/0 to about 15% of the acetaminophen present in the at
least one extended release portion may be released within about 15
minutes, from about 25% to about 40% of the acetaminophen present
in the at least one extended release portion may be released within
about 2 hours, from about 50% to about 65% of the acetaminophen
present in the at least one extended release portion may be
released within about 4 hours, and from about 80% to about 95% of
the acetaminophen present in the at least one extended release
portion may be released within about 8 hours.
[0307] In another embodiment, the at least one extended release
portion of the composition may have in vitro release rates of
acetaminophen as follows: from about 1')/0 to about 10% of the
acetaminophen present in the at least one extended release portion
may be released within about 15 minutes, from about 25% to about
35% of the acetaminophen present in the at least one extended
release portion may be released within about 2 hours, from about
55% to about 65% of the acetaminophen present in the at least one
extended release portion may be released within about 4 hours, and
from about 80% to about 90% of the acetaminophen present in the at
least one extended release portion may be released within about 8
hours.
[0308] In another embodiment, the at least one extended release
portion of the composition may have in vitro release rates of
acetaminophen as follows: from about 1% to about 10% of the
acetaminophen present in the at least one extended release portion
may be released within about 15 minutes, from about 20% to about
50% of the acetaminophen present in the at least one extended
release portion may be released within about 2 hours, from about
35% to about 75% of the acetaminophen present in the at least one
extended release portion may be released within about 4 hours, and
from about 65% to about 100% of the acetaminophen present in the at
least one extended release portion may be released within about 8
hours.
[0309] In one embodiment, the in vitro release rates of oxycodone
from the composition may be as follows: about 20% to about 45% of
oxycodone may be released from the composition within about 15
minutes, from about 50% to about 75% of oxycodone may be released
from the composition in about 2 hours, from about 70% to about 95%
of oxycodone may be released from the composition within about 4
hours, and from about 90% to about 100% of oxycodone may be
released from the composition within about 8 hours.
[0310] In one embodiment, the in vitro release rates of oxycodone
from the composition may be as follows: about 25% to about 35% of
oxycodone may be released from the composition within about 15
minutes, from about 40% to about 80% of oxycodone may be released
from the composition in about 2 hours, from about 70% to about 85%
of oxycodone may be released from the composition within about 4
hours, and from about 90% to about 100% of oxycodone may be
released from the composition within about 8 hours.
[0311] In another embodiment, the pharmaceutical composition
disclosed herein may have in vitro release rates of oxycodone as
follows: about 25% to about 30% of oxycodone may be released from
the pharmaceutical composition within about 15 minutes, from about
50% to about 60% of oxycodone may be released from the
pharmaceutical composition within about 2 hours, from about 70% to
about 80% of oxycodone may be released from the pharmaceutical
composition within about 4 hours, and from about 90% to about 95%
of oxycodone may be released from the pharmaceutical composition
within about 8 hours.
[0312] In one embodiment, the in vitro release rates of
acetaminophen from the composition may be as follows: from about
40% to about 65% of acetaminophen may be released from the
composition in about 15 minutes, from about 55% to about 80% of
acetaminophen may be released from the composition in about 2
hours, from about 65% to about 95% of acetaminophen may be released
from the composition in about 4 hours, and from about 80% to about
100% of acetaminophen may be released from the composition in about
8 hours.
[0313] In one embodiment, the in vitro release rates of
acetaminophen from the composition may be as follows: from about
30% to about 70% of acetaminophen may be released from the
composition in about 15 minutes, from about 50% to about 90% of
acetaminophen may be released from the composition in about 2
hours, from about 60% to about 95% of acetaminophen may be released
from the composition in about 4 hours, and from about 90% to about
100% of acetaminophen may be released from the composition in about
8 hours.
[0314] In another embodiment, the in vitro release rates of
acetaminophen from the pharmaceutical composition disclosed herein
may be as follows: from about 50% to about 55% of acetaminophen may
be released from the pharmaceutical composition within about 15
minutes, from about 60% to about 70% of acetaminophen may be
released from the pharmaceutical composition within about 2 hours,
from about 75% to about 85% of acetaminophen may be released from
the pharmaceutical composition within about 4 hours, and from about
90% to about 100% of acetaminophen may be released from the
pharmaceutical composition within about 8 hours.
[0315] In another embodiment, about 90% to about 100% of the IR
dose of acetaminophen is released within about 15 minutes, 30
minutes, 45 minutes or 60 minutes after oral administration. In one
embodiment, the pharmaceutical composition provides a dissolution
profile wherein about 20% to about 65%, about 35% to about 55% or
about 40% to about 50% of the ER dose of acetaminophen remains in
the ER layer between about 1 and 2 hours after administration.
[0316] In yet another embodiment, the pharmaceutical composition
provides a dissolution profile wherein about 50% to about 95% of
the ER dose of acetaminophen remains in the ER layer between about
1 and 2 hours after administration. In another embodiment, the
dosage form provides a dissolution profile wherein about 15% to
about 40% of the ER dose of acetaminophen is released from the ER
layer between about 1 and 2 hours after administration. In one
embodiment, not more than 50% of the ER dose of acetaminophen is
released within about the first hour. In a further embodiment, not
more than 45% or not more than 40% of the ER dose of acetaminophen
is released within about the first hour.
[0317] In another embodiment, not more than 85% of the ER dose of
acetaminophen is released within about 4 hours. In yet another
embodiment, not less than 50% is released after about 6 hours. In
yet another embodiment, not less than 55% is released after about 6
hours. In one embodiment, the ER dose of acetaminophen is released
over a time period of about 6 to 12, about 8 to 10, or about 9 to
10 hours in vitro. In another embodiment, the ER dose of
acetaminophen is released over a time period of about 7 hours, 8
hours, 9 hours, 10 hours, 11 hours or 12 hours in vitro. In one
embodiment, at least 80% or 85% of the ER dose of acetaminophen is
released over a time period of about 7 hours, 8 hours, 9 hours, 10
hours, 11 hours or 12 hours in vitro. In another embodiment, at
least 90% or 95% of the ER dose of acetaminophen is released over a
time period of about 7 hours, 8 hours, 9 hours, 10 hours, 11 hours
or 12 hours in vitro.
[0318] Additionally, the in vitro release rates of oxycodone and
acetaminophen from the pharmaceutical composition generally are not
affected by low concentrations of ethanol (i.e., from about 5% v/v
to about 20% v/v) when measured in 900 mL of 0.1 N HCl containing
the desired percentage of ethanol using a USP type II paddle
apparatus and at a paddle speed of about 150 rpm and a constant
temperature of 37.degree. C. For example, from about 25% to about
35% of oxycodone and about 50% to about 55% of acetaminophen may be
released from the pharmaceutical composition within about 15
minutes when measured in the presence of 5% to 20% ethanol, and
from about 50% to about 65% of oxycodone and from about 60% to
about 70% of acetaminophen may be released from the pharmaceutical
composition within about 2 hour when measured in the presence of 5%
to 20% ethanol.
[0319] The in vitro release rates of oxycodone and acetaminophen
from the pharmaceutical compositions disclosed herein generally are
reduced, however, in the presence of 40% ethanol. For example, from
about 5% to about 15% of the oxycodone and from about 15% to about
25% of the acetaminophen may be released from the pharmaceutical
composition within about 15 minutes when measured in the presence
of 40% ethanol, and from about 35% to about 45% of oxycodone and
from about 45% to about 55% of acetaminophen may be released from
the pharmaceutical composition within about 2 hours when measured
in the presence of 40% ethanol.
[0320] Stated another way, less oxycodone is extracted from the
pharmaceutical composition by a solution of 0.1 N HCl and 40%
ethanol than is extracted by a solution of 0.1 N HCl. In some
embodiments, less than about 75% of the oxycodone that is released
in the presence of 0.1 N HCl may be released in the presence of 0.1
N HCl containing 40% ethanol. In additional embodiments, less than
about 70%, 65%, 60%, 55%, 50%, 45%, or 40% of the oxycodone that
may be released in the presence of 0.1 N HCl may be released in the
presence of 0.1 N HCl and 40% ethanol. For example, less than about
40% of the oxycodone that may be released in the presence of 0.1 N
HCl in about 15 minutes may be released in the presence of 0.1N HCl
and 40% ethanol within about 15 minutes. In other embodiments, less
than about 60% of the oxycodone that may be released in the
presence of 0.1 N HCl in about 30 minutes may be released in the
presence of 0.1 N HCl and 40% ethanol within about 30 minutes. In
additional embodiments, less than about 75% of the oxycodone that
may be released in the presence of 0.1 N HCl in about 2 hours may
be released in the presence of 0.1 N HCl and 40% ethanol within
about 2 hours.
(g) Stability Data for the Pharmaceutical Composition
[0321] In one embodiment, p-aminophenol may be present in the
pharmaceutical composition as a degradation product of
acetaminophen in any amount up to and including, but no more than,
about 100 ppm. In other embodiments, p-aminophenol may be present
in the pharmaceutical composition as a degradation product of
acetaminophen in an amount of about 0.2 ppm to about 6.0 ppm after
storage for about 1, 2, or 3 months at a temperature of about
25.degree. C. to about 40.degree. C. and at about 60% to about 75%
relative humidity. In yet another embodiment, p-aminophenol may be
present in the pharmaceutical composition as a degradation product
of acetaminophen in an amount of about 0.6 ppm to about 6.0 ppm
after storage for about 1, 2, or 3 months at a temperature of about
25.degree. C. to about 40.degree. C. and at about 60% to about 75%
relative humidity. In still another embodiment, p-aminophenol may
be present in the pharmaceutical composition as a degradation
product of acetaminophen in an amount of about 0.2 ppm, 0.3 ppm,
0.4 ppm, 0.5 ppm, 0.6 ppm, 0.7 ppm, 0.8 ppm, 0.9 ppm, 1.0 ppm, 1.1
ppm, 1.2 ppm, 1.3 ppm, 1.4 ppm, 1.5 ppm, 1.6 ppm, 1.7 ppm, 1.8 ppm,
1.9 ppm, 2.0 ppm, 2.1 ppm, 2.2 ppm, 2.3 ppm, 2.4 ppm, 2.5 ppm, 2.6
ppm, 2.7 ppm, 2.8 ppm, 2.9 ppm, 3.0 ppm, 3.1 ppm, 3.2 ppm, 3.3 ppm,
3.4 ppm, 3.5 ppm, 3.6 ppm, 3.7 ppm, 3.8 ppm, 3.9 ppm, 4.0 ppm, 4.1
ppm, 4.2 ppm, 4.3 ppm, 4.4 ppm, 4.5 ppm, 4.6 ppm, 4.7 ppm, 4.8 ppm,
4.9 ppm, 5.0 ppm, 5.1 ppm, 5.2 ppm, 5.3 ppm, 5.4 ppm, 5.5 ppm, 5.6
ppm, 5.7 ppm, 5.8 ppm, 5.9 ppm, and 6.0 ppm after storage for about
1, 2, or 3 months at a temperature of 25.degree. C. to about
40.degree. C. and at about 60% to about 75% relative humidity
[0322] In one embodiment, oxycodone N-oxide may be present in the
pharmaceutical composition as a degradation product of oxycodone in
any amount up to and including about 0.5% by weight of the
oxycodone. In other embodiments, oxycodone N-oxide may be present
in the pharmaceutical composition as a degradation product of
oxycodone in an amount of about 0.01% to about 0.5% by weight of
the oxycodone after storage for about 1, 2, or 3 months at a
constant temperature of about 25.degree. C. to 40.degree. C. and at
about 60% to 75% relative humidity. In yet another embodiment,
oxycodone N-oxide may be present in the pharmaceutical composition
as a degradation product of oxycodone in an amount of about 0.05%
to about 0.5% by weight of the oxycodone after storage for about 1,
2, or 3 months at a constant temperature of about 25.degree. C. to
40.degree. C. and at about 60% to 75% relative humidity. In
additional embodiments, oxycodone N-oxide may be present in the
pharmaceutical composition as a degradation product of oxycodone in
an amount of about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%,
0.08%, 0.09%, 0.1%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%,
0.17%, 0.18%, 0.19%, 0.2%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%,
0.26%, 0.27%, 0.28%, 0.29%, 0.3%, 0.31%, 0.32%, 0.33%, 0.34%,
0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.4%, 0.41%, 0.42%, 0.43%,
0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, and 0.5% by weight of the
oxycodone after storage for about 1, 2, or 3 months at a constant
temperature of about 25.degree. C. to about 40.degree. C. and at
about 60% to about 75% relative humidity.
[0323] In one embodiment, Related Substance A (i.e.,
C-Normorphinan-6-carboxylic acid,
4,5-epoxy-6,14-dihydroxy-3-methoxy-17-methyl-,
(5.alpha.,6.alpha.)-) may be present in the pharmaceutical
composition as a degradation product of oxycodone in a maximum
amount of about 0.5% by weight of the oxycodone. In other
embodiments, Related Substance A may be present in the
pharmaceutical composition as a degradation product of oxycodone in
an amount of about 0.01% to about 0.5% by weight of the oxycodone
after storage for about 1, 2, or 3 months at a temperature of about
25.degree. C. to about 40.degree. C. and at about 60% to about 75%
relative humidity. In yet another embodiment, Related Substance A
may be present in the pharmaceutical composition as a degradation
product of oxycodone in an amount of about 0.05% to about 0.5% by
weight of the oxycodone after storage for about 1, 2, or 3 months
at a temperature of about 25.degree. C. to about 40.degree. C. and
at about 60% to about 75% relative humidity. In other embodiments,
Related Substance A may be present in the pharmaceutical
composition as a degradation product of oxycodone in an amount of
about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%,
0.09%, 0.1%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%,
0.18%, 0.19%, 0.2%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%,
0.27%, 0.28%, 0.29%, 0.3%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%,
0.36%, 0.37%, 0.38%, 0.39%, 0.4%, 0.41%, 0.42%, 0.43%, 0.44%,
0.45%, 0.46%, 0.47%, 0.48%, 0.49%, and 0.5% by weight of the
oxycodone after storage for about 1, 2, or 3 months at a
temperature of about 25.degree. C. to about 40.degree. C. and at
about 60% to about 75% relative humidity.
[0324] In one embodiment, each unspecified acetaminophen
degradation product may be present in the pharmaceutical
composition in any amount up to about 0.15% by weight of the
acetaminophen. In another embodiment, each unspecified
acetaminophen degradation product may be present in the
pharmaceutical composition as a degradation product of
acetaminophen in an amount of about 0.01% and about 0.15% by weight
of the acetaminophen after storage for about 1, 2, or 3 months at a
temperature of about 25.degree. C. to about 40.degree. C. and at
about 60% to about 75% relative humidity. In still another
embodiment, each unspecified acetaminophen degradation product may
be present in the pharmaceutical composition as a degradation
product of acetaminophen in an amount of about 0.05% and about
0.15% by weight of the acetaminophen after storage for about 1, 2,
or 3 months at a temperature of about 25.degree. C. to about
40.degree. C. and at about 60% to about 75% relative humidity. In
other embodiments, each unspecified acetaminophen degradation
product may be present in the pharmaceutical composition as a
degradation product of acetaminophen in an amount of about 0.01%,
0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%,
0.11%, 0.12%, 0.13%, 0.14%, and 0.15% by weight of the
acetaminophen after storage for about 1, 2, or 3 months at a
temperature of about 25.degree. C. to about 40.degree. C. and at
about 60% to about 75% relative humidity.
[0325] In one embodiment, each unspecified oxycodone HCl
degradation product may be present in the pharmaceutical
composition in a maximum amount of about 0.2% by weight of the
oxycodone. In other embodiments, each unspecified oxycodone HCl
degradation product may be present in the pharmaceutical
composition in an amount of about 0.01% to about 0.2% by weight of
the oxycodone after storage for about 1, 2, or 3 months at a
temperature of about 25.degree. C. to about 40.degree. C. and at
about 60% to about 75% relative humidity. In yet another
embodiment, each unspecified oxycodone HCl degradation product may
be present in the pharmaceutical composition in an amount of about
0.05% to about 0.2% by weight of the oxycodone after storage for
about 1, 2, or 3 months at a temperature of about 25.degree. C. to
about 40.degree. C. and at about 60% to about 75% relative
humidity. In further embodiments, each unspecified oxycodone HCl
degradation product may be present in the pharmaceutical
composition in an amount of about 0.01%, 0.02%, 0.03%, 0.04%,
0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%,
0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, and 0.2% by weight of the
oxycodone after storage for about 1, 2, or 3 months at a
temperature of about 25.degree. C. to about 40.degree. C. and at
about 60% to about 75% relative humidity.
[0326] In one embodiment, the total acetaminophen degradation
products may be present in the pharmaceutical composition in a
maximum amount of about 1.0% by weight of the acetaminophen. In
other embodiments, the total acetaminophen degradation products may
be present in the pharmaceutical composition in an amount of about
0.05% to about 1.0% by weight of the acetaminophen after storage
for about 1, 2, or 3 months at a temperature of about 25.degree. C.
to about 40.degree. C. and at about 60% to about 75% relative
humidity. In further embodiments, the total acetaminophen
degradation products may be present in the pharmaceutical
composition in an amount of about 0.05%, 0.1%, 0.15%, 0.2%, 0.25%,
0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%,
0.8%, 0.85%, 0.9%, 0.95%, and 1.0% by weight of the acetaminophen
after storage for about 1, 2, or 3 months at a temperature of about
25.degree. C. to about 40.degree. C. and at about 60% to about 75%
relative humidity.
[0327] In one embodiment, the total oxycodone degradation products
may be present in the pharmaceutical composition in a maximum
amount of about 1.0% by weight of the oxycodone. In further
embodiments, the total oxycodone degradation products may be
present in the pharmaceutical composition in an amount of about
0.05% to about 1.0% by weight of the oxycodone after storage for
about 1, 2, or 3 months at a temperature of about 25.degree. C. to
about 40.degree. C. and at about 60% to about 75% relative
humidity. In yet other embodiments, the total oxycodone degradation
products may be present in the pharmaceutical composition in an
amount of about 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%,
0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%,
0.95%, and 1.0% by weight of the oxycodone after storage for about
1, 2, or 3 months at a temperature of about 25.degree. C. to about
40.degree. C. and at about 60% to about 75% relative humidity.
(h) In Vivo and Pharmacokinetic Properties of the Pharmaceutical
Composition
[0328] The pharmaceutical composition disclosed herein comprises at
least one immediate release portion for immediate release of
oxycodone and acetaminophen such that therapeutic plasma
concentrations are quickly attained (e.g., within one hour) and the
initial onset of action is achieved within about 5 minutes, 10
minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35
minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, or 60
minutes after administration of the composition upon oral
administration to a subject. The pharmaceutical composition
disclosed herein also comprises at least one extended release
portion for sustained release of oxycodone and acetaminophen over
an extended period of time, e.g., about 3 to about 12 hours, or
about 4 to about 9 hours, or at least about 6 hours, or at least
about 8 hours, to the upper gastrointestinal tract where
acetaminophen, and potentially oxycodone, is best absorbed.
[0329] The pharmaceutical composition may be orally administered to
a subject once in a 24 hour period (q.d. or once-daily), two times
in a 24 hour period (b.i.d. or twice-daily), or three times in a 24
hour period (t.i.d. or three times daily). In one embodiment, the
pharmaceutical composition may be orally administered to the
subject twice a day (i.e., every 12 hours). In another embodiment,
the pharmaceutical composition may be orally administered to the
subject at time zero (t=0), and then the subject may be
administered a subsequent dose of the pharmaceutical composition
either after eight hours (t=8) or twelve hours (t=12). The subject
may be a mammal, and in certain embodiments, the subject may be a
human.
[0330] In another embodiment, the subject may be administered a
first or loading dose of the pharmaceutical composition. This first
or loading dose may assist the subject in more quickly attaining
steady state blood levels of the active drugs. In a further
embodiment, the subject may be administered a first or loading dose
of the pharmaceutical composition comprising about 22.5 mg of
oxycodone and about 975 mg of acetaminophen. In yet another
embodiment, the subject may be administered a first or loading dose
of the pharmaceutical composition comprising 2 tablets, each tablet
comprising about 11.25 mg of oxycodone and about 462.5 mg of
acetaminophen. In yet another embodiment, the subject may be
administered a first or loading dose of the pharmaceutical
composition comprising 3 tablets, each tablet comprising about 7.5
mg of oxycodone and about 325 mg of acetaminophen. In still another
embodiment, the subject may be administered a first or loading dose
of the pharmaceutical composition comprising 4 tablets, each tablet
comprising about 5.625 mg of oxycodone and about 231.25 mg of
acetaminophen. In yet another embodiment, the subject may be
administered a first or loading dose of the pharmaceutical
composition comprising 2 capsules, each capsule comprising about
11.25 mg of oxycodone and about 462.5 mg of acetaminophen. In yet
another embodiment, the subject may be administered a first or
loading dose of the pharmaceutical composition comprising 3
capsules, each capsules comprising about 7.5 mg of oxycodone and
about 325 mg of acetaminophen. In still another embodiment, the
subject may be administered a first or loading dose of the
pharmaceutical composition comprising 4 capsules, each capsules
comprising about 5.625 mg of oxycodone and about 231.25 mg of
acetaminophen.
[0331] Upon oral administration to a subject, the pharmaceutical
composition disclosed herein may maintain a therapeutic blood
plasma concentration of oxycodone of at least about 5 ng/mL from
about 0.75 hours to about 12 hours after administration of the
composition. In another embodiment, the plasma concentration of
oxycodone may be maintained at a concentration of at least about
7.5 ng/mL from about 1 hour to about 12 hours after administration
of the composition. In a further embodiment, the plasma
concentration of oxycodone may be maintained at a concentration of
at least about 7.5 ng/mL from about 0.75 hour to about 10 hours
after administration of the composition. In a further embodiment,
the plasma concentration of oxycodone may be maintained at a
concentration of at least about 10 ng/mL from about 2 hour to about
10 hours after administration of the composition. In yet another
embodiment, the plasma concentration of oxycodone may be maintained
at a concentration of at least about 10 ng/mL from about 1 hour to
about 10 hours after administration of the composition. In still
another embodiment, the plasma concentration of oxycodone may be
maintained at a concentration of at least about 10 ng/mL from about
0.75 hour to about 10 hours after administration of the
composition.
[0332] In another embodiment, the pharmaceutical composition, when
orally administered to a subject, may produce a plasma profile
characterized by a mean C.sub.max (peak plasma concentration) for
oxycodone from about 0.9 ng/mL/mg to about 1.6 ng/mL/mg. In another
embodiment, the mean C.sub.max for oxycodone may range from about
1.0 ng/mL/mg to about 1.5 ng/mL/mg. In an additional embodiment,
the mean C.sub.max for oxycodone may be about 0.9, 1.0, 1.1, 1.2,
1.3, 1.4, 1.5, or 1.6 ng/mL/mg. Moreover, the mean C.sub.max for
oxycodone at steady state may range from about 1.5 ng/mL/mg to
about 2.0 ng/mL/mg, from about 1.6 ng/mL/mg to about 1.95 ng/mL/mg,
or from about 1.7 ng/mL/mg to about 1.85 ng/mL/mg.
[0333] In a further embodiment, the pharmaceutical composition,
when orally administered to a subject, surprisingly may produce a
blood plasma concentration profile characterized by a biphasic
increase in blood plasma concentrations of oxycodone. Deconvolution
of the pharmaceutical composition and the target plasma profiles
can be done in WinNonLin (version 5.2, Pharsight Corp., Mountain
View, Calif.). The results of such a deconvolution analysis for
oxycodone is depicted in FIG. 23. The biphasic absorption of
oxycodone may be characterized by an initial rapid absorption
resulting in a first peak in plasma concentration between about 1
hour and 2 hours, which contributes to the early onset of action,
and a second peak in plasma concentrations between about 3 hours
and 7 hours as a result of slower absorption taking place from the
at least one extended release portion after administration of the
composition, which contributes to the duration or maintenance of
analgesia. In some instances, the second peak may correspond to the
overall C.sub.max of the composition. The biphasic increase in
blood plasma concentrations of oxycodone may be characterized by a
plasma concentration-time profile for oxycodone in which the slope
of a line drawn between 0 hour and about 2 hours is greater than
the slope of a line drawn between about 2 hours and about 5 hours.
See FIG. 23.
[0334] This biphasic increase in oxycodone levels resulting from
the composition has several benefits. For example, providing rapid
but not too high concentrations of oxycodone for quick onset of
analgesia followed by maintenance of oxycodone levels over an
extended time period could prevent a human subject from developing
liking or dependence (abuse) for oxycodone. Further fluctuations in
the oxycodone plasma levels could also prevent development of
tolerance at the active site. Thus, the biphasic increase in
oxycodone levels helps to prevent this acute tolerance.
[0335] In an additional embodiment, the pharmaceutical composition,
when orally administered to a subject, may produce a plasma profile
characterized by a mean AUC for oxycodone from about 9.0 nghr/mL/mg
to about 18.5 nghr/mL/mg. In a further embodiment, the mean AUC for
oxycodone may be from about 12.0 nghr/mL/mg to about 16.0
nghr/mL/mg. In another embodiment, the mean AUC for oxycodone may
be about 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5,
14.0, 14.5, 15.0, 15.5, or 16.0 nghr/mL/mg. Additionally, the mean
AUC for oxycodone at steady state may range from about 11.0
nghr/mL/mg to about 17.0 nghr/mL/mg, from about 12.0 nghr/mL/mg to
about 16.0 nghr/mL/mg, or from about 13.0 nghr/mL/mg to about 15.0
nghr/mL/mg.
[0336] In a further embodiment, the pharmaceutical composition,
when orally administered to a subject, may produce a plasma profile
characterized by a median T.sub.max (time to peak plasma
concentration) for oxycodone from about 2.0 hours to about 7.0
hours. In an alternate embodiment, the median T.sub.max for
oxycodone may be from about 3.0 hours to about 6.0 hours. In
another embodiment, the median T.sub.max for oxycodone may be about
2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5 or 6.0 hours. Moreover, the
median T.sub.max for oxycodone at steady state may range from about
1.5 hours to about 3.5 hours, or from about 2 hours to about 3
hours.
[0337] In still another embodiment, the pharmaceutical composition,
when orally administered to a subject, may produce a plasma profile
characterized by a median tlag for oxycodone from about 0 hours to
about 0.5 hours. In an alternate embodiment, the median tlag for
oxycodone may be from about 0 hours to about 0.25 hours.
[0338] Rates of absorption are often assessed by comparing standard
pharmacokinetic parameters such as T.sub.max and C.sub.max. The
extent of absorption is assessed by the AUC. A short Tmax has been
used to indicate rapid absorption. The U.S. FDA, Guidance for
Industry: Bioavailability and Bioequivalence Studies for Orally
Administered Drug Products--General Considerations (March 2003) and
related publications (Chen et al, Clin. Pharmacokinet.
40(8):565-72, 2001) also recommends the use of partial AUC for some
modified-release drugs ("MR drugs"), such as the pharmaceutical
compositions disclosed herein. A partial AUC calculation may be
used to measure early exposure to a drug, which may signify an
initial onset of pain relief and/or to measure prolonged exposure
of a drug in achieving sustained relief. Partial AUC calculations
can also demonstrate whether two MR drugs are truly bioequivalent
by comparing, for example, an early partial AUC, which will be
associated with a drug's response onset, and a late partial AUC,
which will be associated with a drug's sustained response. The
parameters for compositions vary greatly between subjects. The
parameters also vary depending on aspects of the study protocol
such as the sampling scheduling, subject posture and general
subject health. Values quoted in this specification are given as
mean.+-.standard deviation unless otherwise noted.
[0339] For partial AUC calculations, the standard linear
trapezoidal summation over each time interval is used. The partial
AUCs are calculated from the mean pharmacokinetic profile. For time
0 to 1 hour the partial AUC is AUC(0-1 hr); for time 0 to 2 hours
the partial AUC is AUC.sub.(0-2hr); for time 0-4 hours the partial
AUC is AUC.sub.(0-4hr); for time 0 to 6 hour the partial AUC is
AUC.sub.(0-6hr); for f time 0 to 8 hours the partial AUC is
AUC.sub.(0-8hr); and for time 0 to the last measurable time point
("x") the partial AUC is AUC(0-(x)hr) where each partial AUC is
calculated according to standard pharmaceutical industry
pharmacokinetic calculation methodologies as given by:
[0340] AUC.sub.(0-1hr)--Area under the drug concentration-time
curve calculated using linear trapezoidal summation from time zero
to time 1 hour.
[0341] AUC.sub.(0-2hr)--Area under the drug concentration-time
curve calculated using linear trapezoidal summation from time zero
to time 2 hours.
[0342] AUC.sub.(0-4hr)--Area under the drug concentration-time
curve calculated using linear trapezoidal summation from time zero
to time 4 hours.
[0343] AUC.sub.(0-6hr)--Area under the drug concentration-time
curve calculated using linear trapezoidal summation from time zero
to time 6 hours.
[0344] AUC.sub.(0-8hr)--Area under the drug concentration-time
curve calculated using linear trapezoidal summation from time zero
to time 8 hours.
[0345] AUC.sub.0-(t)hr)--Area under the drug concentration-time
curve calculated using linear trapezoidal summation from time zero
to the last measurable time point.
[0346] AUC.sub.(0-(Tmax of IR product+2SD))--Area under the drug
concentration-time curve calculated using linear trapezoidal
summation from time zero to the time of the mean peak (Tmax) for
the immediate release version of the drug plus two standard
deviations ("2SD") for the immediate release drug. The FDA has
identified this calculation in association with an early onset of
response for certain modified-release dosage forms, which show
complex pharmacokinetic characteristics. (See supra March 2003
Guidance; Draft Guidance on Dexmethylphenidate Hydrochloride (March
2012); Draft Guidance on Methylphenidate Hydrocholoride (November
2011)).
[0347] AUC.sub.((Tmax of IR product+2SD)-t)--Area under the drug
concentration-time curve calculated using linear trapezoidal
summation from the time of the mean peak (T.sub.max) for the
immediate release version of the drug plus two standard deviations
("2SD") for the immediate release drug to the last measurable time
point. The FDA has identified this parameter in association with
sustaining the response for modified-release dosage forms, which
shows complex pharmacokinetic characteristics. (See March 2003
Guidance supra; Draft Guidance on Dexmethylphenidate Hydrochloride
(March 2012); Draft Guidance on Methylphenidate Hydrocholoride
(November 2011)).
[0348] AUC.sub.(x-(y)hr--Area under the drug concentration-time
curve calculated using linear trapezoidal summation from time "x"
(e.g., any measurable time point, such as 8 hours) to time "y"
(e.g., any other measurable time point later than "x", such as 12
hours).
[0349] AUC.sub.(0-.infin.)--Area under the drug concentration-time
curve calculated using linear trapezoidal summation from time 0 to
infinity.
[0350] Further, partial AUC may be calculated using trapezoidal
summation from time Tmax to time t (the last measured time point of
plasma concentration profile).
[0351] In one embodiment, the pharmaceutical composition, when
orally administered to a subject, may produce a plasma profile
characterized by an AUC.sub.0-1hr for oxycodone from about 0.10
nghr/mL/mg to about 0.45 nghr/mL/mg, from about 0.15 nghr/mL/mg to
about 0.25 nghr/mL/mg, or from about 0.25 nghr/mL/mg to about 0.35
nghr/mL/mg. In another embodiment, the AUC.sub.0-1hr for oxycodone
may be about 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, or 0.45
nghr/mL/mg.
[0352] In an additional embodiment, the pharmaceutical composition,
when orally administered to a subject, may produce a plasma profile
characterized by an AUC.sub.0-2hr for oxycodone from about 0.65
nghr/mL/mg to about 1.50 nghr/mL/mg, from about 0.80 nghr/mL/mg to
about 1.0 nghr/mL/mg, or from about 1.0 nghr/mL/mg to about 1.2
nghr/mL/mg. In another embodiment, the AUC.sub.0-2hr for oxycodone
may be about 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.0, 1.05,
1.10, 1.15, 1.20, 1.25, 1.30, 1.35, 1.40, 1.45, or 1.50
nghr/mL/mg.
[0353] In an additional embodiment, the pharmaceutical composition,
when orally administered to a subject under fasted conditions, may
produce a plasma profile characterized by an AUC.sub.0-2hr for
oxycodone from about 0.8 nghr/mL/mg to about 1.50 nghr/mL/mg, from
about 0.80 nghr/mL/mg to about 1.0 nghr/mL/mg, or from about 1.0
nghr/mL/mg to about 1.2 nghr/mL/mg. In another embodiment, the
AUC.sub.0-2hr for oxycodone may be about 0.80, 0.85, 0.90, 0.95,
1.0, 1.05, 1.10, 1.15, 1.20, 1.25, 1.30, 1.35, 1.40, 1.45, or 1.50
nghr/mL/mg.
[0354] In a further embodiment, the pharmaceutical composition,
when orally administered to a subject under fed conditions (high
fat meal), may produce a plasma profile characterized by an
AUC.sub.0-2hr for oxycodone from about 0.65 nghr/mL/mg to about
1.30 nghr/mL/mg, from about 0.80 nghr/mL/mg to about 1.0
nghr/mL/mg, or from about 1.0 nghr/mL/mg to about 1.2 nghr/mL/mg.
In another embodiment, the AUC.sub.0-2hr for oxycodone may be about
0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.0, 1.05, 1.10, 1.15,
1.20, 1.25, or 1.30 nghr/mL/mg.
[0355] In a further embodiment, the pharmaceutical composition,
when orally administered to a subject under fed conditions (low fat
meal), may produce a plasma profile characterized by an
AUC.sub.0-2hr for oxycodone from about 0.65 nghr/mL/mg to about
1.30 nghr/mL/mg, from about 0.80 nghr/mL/mg to about 1.0
nghr/mL/mg, or from about 1.0 nghr/mL/mg to about 1.2 nghr/mL/mg.
In another embodiment, the AUC.sub.0-2hr for oxycodone may be about
0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.0, 1.05, 1.10, 1.15,
1.20, 1.25, or 1.30 nghr/mL/mg.
[0356] In an additional embodiment, the pharmaceutical composition,
when orally administered to a subject, may produce a plasma profile
characterized by an AUC.sub.2-48hr for oxycodone from about 8.0
nghr/mL/mg to about 17.8 nghr/mL/mg, from about 10.0 nghr/mL/mg to
about 11.0 nghr/mL/mg, or from about 11.0 nghr/mL/mg to about 12.0
nghr/mL/mg, or from about 12.0 nghr/mL/mg to about 13.0 nghr/mL/mg,
or from about 13.0 nghr/mL/mg to about 14.0 nghr/mL/mg, or from
about 14.0 nghr/mL/mg to about 15.0 nghr/mL/mg. In another
embodiment, the AUC.sub.2-48hr for oxycodone may be about 8.0, 8.1,
8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4,
9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6,
10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7,
11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8,
12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9,
14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0,
15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16.0, 16.1,
16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2,
17.3, 17.4, 17.5, 17.6, 17.7, or 17.8 nghr/mL/mg.
[0357] In an additional embodiment, the pharmaceutical composition,
when orally administered to a subject under fasted conditions, may
produce a plasma profile characterized by an AUC.sub.2-48hr for
oxycodone from about 8.0 nghr/mL/mg to about 15.1 nghr/mL/mg, from
about 10.0 nghr/mL/mg to about 11.0 nghr/mL/mg, or from about 11.0
nghr/mL/mg to about 12.0 nghr/mL/mg, or from about 12.0 nghr/mL/mg
to about 13.0 nghr/mL/mg, or from about 13.0 nghr/mL/mg to about
14.0 nghr/mL/mg, or from about 14.0 nghr/mL/mg to about 15.0
nghr/mL/mg. In another embodiment, the AUC.sub.2-48hr for oxycodone
may be about 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0,
9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2,
10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3,
11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4,
12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5,
13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6,
14.7, 14.8, 14.9, 15.0, or 15.1 nghr/mL/mg.
[0358] In an additional embodiment, the pharmaceutical composition,
when orally administered to a subject under fed conditions (high
fat meal), may produce a plasma profile characterized by an
AUC.sub.2-48hr for oxycodone from about 9.5 nghr/mL/mg to about
17.8 nghr/mL/mg, from about 10.0 nghr/mL/mg to about 11.0
nghr/mL/mg, or from about 11.0 nghr/mL/mg to about 12.0 nghr/mL/mg,
or from about 12.0 nghr/mL/mg to about 13.0 nghr/mL/mg, or from
about 13.0 nghr/mL/mg to about 14.0 nghr/mL/mg, or from about 14.0
nghr/mL/mg to about 15.0 nghr/mL/mg, or from about 14.0 nghr/mL/mg
to about 15.0 nghr/mL/mg. In another embodiment, the AUC.sub.2-48hr
for oxycodone may be about 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1,
10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2,
11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3,
12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4,
13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5,
14.6, 14.7, 14.8, 14.9, 15.0, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6,
15.7, 15.8, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7,
16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, or 17.8
nghr/mL/mg.
[0359] In an additional embodiment, the pharmaceutical composition,
when orally administered to a subject under fed conditions (low fat
meal), may produce a plasma profile characterized by an
AUC.sub.2-48hr for oxycodone from about 9.5 nghr/mL/mg to about
17.8 nghr/mL/mg, from about 10.0 nghr/mL/mg to about 11.0
nghr/mL/mg, or from about 11.0 nghr/mL/mg to about 12.0 nghr/mL/mg,
or from about 12.0 nghr/mL/mg to about 13.0 nghr/mL/mg, or from
about 13.0 nghr/mL/mg to about 14.0 nghr/mL/mg, or from about 14.0
nghr/mL/mg to about 15.0 nghr/mL/mg, or from about 14.0 nghr/mL/mg
to about 15.0 nghr/mL/mg. In another embodiment, the AUC.sub.2-48hr
for oxycodone may be about 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1,
10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2,
11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3,
12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4,
13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5,
14.6, 14.7, 14.8, 14.9, 15.0, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6,
15.7, 15.8, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7,
16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, or 17.8
nghr/mL/mg.
[0360] In an additional embodiment, the pharmaceutical composition,
when orally administered to a subject, may produce a plasma profile
characterized by an AUC.sub.8-10hr for oxycodone from about 0.90
nghr/mL/mg to about 2.30 nghr/mL/mg, from about 0.80 nghr/mL/mg to
about 1.0 nghr/mL/mg, or from about 1.0 nghr/mL/mg to about 1.2
nghr/mL/mg, or from about 1.2 nghr/mL/mg to about 1.4 nghr/mL/mg,
or from about 1.4 nghr/mL/mg to about 1.6 nghr/mL/mg, or from about
1.6 nghr/mL/mg to about 1.8 nghr/mL/mg, or from about 1.6
nghr/mL/mg to about 1.8 nghr/mL/mg, or from about 1.8 nghr/mL/mg to
about 2.0 nghr/mL/mg. In another embodiment, the AUC.sub.8-10hr for
oxycodone may be about 0.90, 0.95, 1.0, 1.05, 1.10, 1.15, 1.20,
1.25, 1.30, 1.35, 1.40, 1.45, 1.50, 1.55, 1.60, 1.65, 1.70, 1.75,
1.80, 1.85, 1.90, 1.95, 2.0, 2.05, 2.10, 2.15, 2.20, 2.25, or 2.30
nghr/mL/mg.
[0361] In an additional embodiment, the pharmaceutical composition,
when orally administered to a subject under fasted conditions, may
produce a plasma profile characterized by an AUC.sub.8-10hr for
oxycodone from about 0.90 nghr/mL/mg to about 1.70 nghr/mL/mg, from
about 0.90 nghr/mL/mg to about 1.0 nghr/mL/mg, or from about 1.0
nghr/mL/mg to about 1.2 nghr/mL/mg, or from about 1.2 nghr/mL/mg to
about 1.4 nghr/mL/mg, or from about 1.4 nghr/mL/mg to about 1.6
nghr/mL/mg. In another embodiment, the AUC.sub.8-10hr for oxycodone
may be about 0.90, 0.95, 1.0, 1.05, 1.10, 1.15, 1.20, 1.25, 1.30,
1.35, 1.40, 1.45, 1.50, 1.55, 1.60, 1.65, or 1.70 nghr/mL/mg.
[0362] In an additional embodiment, the pharmaceutical composition,
when orally administered to a subject under fed conditions (high
fat meal), may produce a plasma profile characterized by an
AUC.sub.8-10hr for oxycodone from about 1.15 nghr/mL/mg to about
2.30 nghr/mL/mg, or from about 1.2 nghr/mL/mg to about 1.4
nghr/mL/mg, or from about 1.4 nghr/mL/mg to about 1.6 nghr/mL/mg,
or from about 1.6 nghr/mL/mg to about 1.8 nghr/mL/mg, or from about
1.8 nghr/mL/mg to about 2.0 nghr/mL/mg. In another embodiment, the
AUC.sub.8-10hr for oxycodone may be about 1.15, 1.20, 1.25, 1.30,
1.35, 1.40, 1.45, 1.50, 1.55, 1.60, 1.65, 1.70, 1.75, 1.80, 1.85,
1.90, 1.95, 2.0, 2.05, 2.10, 2.15, 2.20, 2.25, or 2.30
nghr/mL/mg.
[0363] In an additional embodiment, the pharmaceutical composition,
when orally administered to a subject under fed conditions (low fat
meal), may produce a plasma profile characterized by an
AUC.sub.8-10hr for oxycodone from about 1.20 nghr/mL/mg to about
2.30 nghr/mL/mg, or from about 1.2 nghr/mL/mg to about 1.4
nghr/mL/mg, or from about 1.4 nghr/mL/mg to about 1.6 nghr/mL/mg,
or from about 1.6 nghr/mL/mg to about 1.8 nghr/mL/mg, or from about
1.8 nghr/mL/mg to about 2.0 nghr/mL/mg. In another embodiment, the
AUC.sub.8-10hr for oxycodone may be about 1.20, 1.25, 1.30, 1.35,
1.40, 1.45, 1.50, 1.55, 1.60, 1.65, 1.70, 1.75, 1.80, 1.85, 1.90,
1.95, 2.0, 2.05, 2.10, 2.15, 2.20, 2.25, or 2.30 nghr/mL/mg.
[0364] In an additional embodiment, the pharmaceutical composition,
when orally administered to a subject, may produce a plasma profile
characterized by an AUC.sub.10-12hr for oxycodone from about 0.70
nghr/mL/mg to about 2.0 nghr/mL/mg, from about 0.80 nghr/mL/mg to
about 1.0 nghr/mL/mg, or from about 1.0 nghr/mL/mg to about 1.2
nghr/mL/mg, or from about 1.2 nghr/mL/mg to about 1.4 nghr/mL/mg,
or from about 1.4 nghr/mL/mg to about 1.6 nghr/mL/mg, or from about
1.6 nghr/mL/mg to about 1.8 nghr/mL/mg, or from about 1.6
nghr/mL/mg to about 1.8 nghr/mL/mg. In another embodiment, the
AUC.sub.10-12hr for oxycodone may be about 0.70, 0.75, 0.80, 0.85,
0.90, 0.95, 1.0, 1.05, 1.10, 1.15, 1.20, 1.25, 1.30, 1.35, 1.40,
1.45, 1.50, 1.55, 1.60, 1.65, 1.70, 1.75, 1.80, 1.85, 1.90, 1.95,
or 2.0 nghr/mL/mg.
[0365] In an additional embodiment, the pharmaceutical composition,
when orally administered to a subject under fasted conditions, may
produce a plasma profile characterized by an AUC.sub.10-12hr for
oxycodone from about 0.70 nghr/mL/mg to about 1.4 nghr/mL/mg, from
about 0.80 nghr/mL/mg to about 1.0 nghr/mL/mg, or from about 1.0
nghr/mL/mg to about 1.2 nghr/mL/mg, or from about 1.2 nghr/mL/mg to
about 1.4 nghr/mL/mg. In another embodiment, the AUC.sub.10-12hr
for oxycodone may be about 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.0,
1.05, 1.10, 1.15, 1.20, 1.25, 1.30, 1.35, or 1.40 nghr/mL/mg.
[0366] In an additional embodiment, the pharmaceutical composition,
when orally administered to a subject under fed conditions (high
fat meal), may produce a plasma profile characterized by an
AUC.sub.10-12hr for oxycodone from about 1.0 nghr/mL/mg to about
1.95 nghr/mL/mg, or from about 1.0 nghr/mL/mg to about 1.2
nghr/mL/mg, or from about 1.2 nghr/mL/mg to about 1.4 nghr/mL/mg,
or from about 1.4 nghr/mL/mg to about 1.6 nghr/mL/mg, or from about
1.6 nghr/mL/mg to about 1.8 nghr/mL/mg. In another embodiment, the
AUC.sub.10-12hr for oxycodone may be about 1.0, 1.05, 1.10, 1.15,
1.20, 1.25, 1.30, 1.35, 1.40, 1.45, 1.50, 1.55, 1.60, 1.65, 1.70,
1.75, 1.80, 1.85, 1.90, or 1.95 nghr/mL/mg.
[0367] In an additional embodiment, the pharmaceutical composition,
when orally administered to a subject under fed conditions (low fat
meal), may produce a plasma profile characterized by an
AUC.sub.10-12hr for oxycodone from about 0.95 nghr/mL/mg to about
1.85 nghr/mL/mg, or from about 1.0 nghr/mL/mg to about 1.2
nghr/mL/mg, or from about 1.2 nghr/mL/mg to about 1.4 nghr/mL/mg,
or from about 1.4 nghr/mL/mg to about 1.6 nghr/mL/mg, or from about
1.6 nghr/mL/mg to about 1.8 nghr/mL/mg. In another embodiment, the
AUC.sub.10-12hr for oxycodone may be about 0.95, 1.0, 1.05, 1.10,
1.15, 1.20, 1.25, 1.30, 1.35, 1.40, 1.45, 1.50, 1.55, 1.60, 1.65,
1.70, 1.75, 1.80, or 1.85 nghr/mL/mg.
[0368] In a further embodiment, the pharmaceutical composition,
when orally administered to a subject, may produce a plasma profile
characterized by an AUC.sub.0-4hr for oxycodone from about 2.0
nghr/mL/mg to about 4.0 nghr/mL/mg, from about 2.5 nghr/mL/mg to
about 3.0 nghr/mL/mg, or from about 3.0 nghr/mL/mg to about 3.5
nghr/mL/mg. In another embodiment, the AUC.sub.0-4hr for oxycodone
may be about 2.0, 2.5, 3.0, 3.5, or 4.0 nghr/mL/mg.
[0369] In yet another embodiment, the pharmaceutical composition,
when orally administered to a subject, may produce a plasma profile
characterized by an AUC.sub.Tmax-t for oxycodone from about 5.0
nghr/mL/mg to about 16.0 nghr/mL/mg, from about 8.0 nghr/mL/mg to
about 10.5 nghr/mL/mg, or from about 10.5 nghr/mL/mg to about 14.0
nghr/mL/mg. In another embodiment, the AUC.sub.Tmax-t for oxycodone
may be about 5.0, 6.0, 7.0, 8.0, 9.0, 10.0, 11.0, 12.0, 12.5, 13.0,
13.5, 14.0, 14.5, 15.0 or 16.0 nghr/mL/mg.
[0370] In still another embodiment, the pharmaceutical composition,
when orally administered to a subject, may produce a plasma profile
characterized by an AUC.sub.(0-(Tmax of IR product+2SD)) for
oxycodone after a single dose from about 1.0 nghr/mL/mg to about
3.0 nghr/mL/mg, from about 1.50 nghr/mL/mg to about 2.5 nghr/mL/mg,
or from about 1.75 nghr/mL/mg to about 2.25 nghr/mL/mg. In another
embodiment, the AUC.sub.(0-(Tmax of IR product+2SD)) for oxycodone
may be about 1.25, 1.3, 1.35, 1.4, 1.45, 1.5, 1.55, 1.6, 1.65, 1.7,
1.75, 1.8, 1.85, 1.9, 1.95, 2.0, 2.05, 2.1, 2.15, 2.2, 2.25, 2.3,
2.35, 2.4, 2.45, 2.5, 2.55, 2.6, 2.65, 2.7, or 2.75 nghr/mL/mg.
[0371] In one embodiment, the immediate release product referenced
for the Partial AUC calculations is Percocet in the fasted state
and the following calculation was used to determine
AUC.sub.(0-(Tmax of IR product+2SD)):
oxycodone mean.+-.SD=1.0 h.+-.0.89 h; Tmax+2SD=2.8 hours
In such embodiment, the pharmaceutical composition, when orally
administered to a subject, may produce a plasma profile
characterized by an AUC.sub.(0-2.8) for oxycodone after a single
dose from about 1.0 nghr/mL/mg to about 3.0 nghr/mL/mg, from about
1.50 nghr/mL/mg to about 2.5 nghr/mL/mg, or from about 1.75
nghr/mL/mg to about 2.25 nghr/mL/mg. In another embodiment, the
AUC.sub.(0-2.8) for oxycodone may be about 1.25, 1.3, 1.35, 1.4,
1.45, 1.5, 1.55, 1.6, 1.65, 1.7, 1.75, 1.8, 1.85, 1.9, 1.95, 2.0,
2.05, 2.1, 2.15, 2.2, 2.25, 2.3, 2.35, 2.4, 2.45, 2.5, 2.55, 2.6,
2.65, 2.7, or 2.75 nghr/mL/mg.
[0372] In yet another embodiment, the pharmaceutical composition,
when orally administered to a subject, may produce a plasma profile
characterized by an AUC.sub.(28-48) for oxycodone after a single
dose from about 7.5 nghr/mL/mg to about 15.0 nghr/mL/mg, from about
8.45 nghr/mL/mg to about 13.7 nghr/mL/mg, or from about 9.5
nghr/mL/mg to about 11.5 nghr/mL/mg. In another embodiment, the
AUC.sub.(28-48) for oxycodone may be about 7.5, 7.6, 7.7, 7.8, 7.9,
8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2,
9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4,
10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5,
11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, or 12.5
nghr/mL/mg.
[0373] In one embodiment, the immediate release product referenced
for the Partial AUC calculations is Percocet in the fed state and
the following calculation was used to determine AUC.sub.(0-(Tmax of
IR product+2SD)):
oxycodone mean.+-.SD=1.9 h.+-.1.2 h; Tmax+2SD=4.3 hours
In such embodiment, the pharmaceutical composition, when orally
administered to a subject, may produce a plasma profile
characterized by an AUC.sub.(0-4.3) for oxycodone after a single
dose from about 1.5 nghr/mL/mg to about 5.5 nghr/mL/mg, from about
2.0 nghr/mL/mg to about 5.0 nghr/mL/mg, from about 2.5 nghr/mL/mg
to about 4.5 nghr/mL/mg, or from about 3.0 nghr/mL/mg to about 4.0
nghr/mL/mg. In another embodiment, the AUC.sub.(0-4.3) for
oxycodone may be about 1.5, 1.55, 1.6, 1.65, 1.7, 1.75, 1.8, 1.85,
1.9, 1.95, 2.0, 2.05, 2.1, 2.15, 2.2, 2.25, 2.3, 2.35, 2.4, 2.45,
2.5, 2.55, 2.6, 2.65, 2.7, 2.75, 2.8, 2.85, 2.9, 2.95, 3.0, 3.05,
3.1, 3.15, 3.2, 3.25, 3.3, 3.35, 3.4, 3.45, 3.5, 3.55, 3.6, 3.65,
3.7, 3.75, 3.8, 3.85, 3.9, 3.95, 4.0, 4.05, 4.1, 4.15, 4.2, 4.25,
4.3, 4.35, 4.4, 4.45, 4.5, 4.55, 4.6, 4.65, 4.7, 4.75, 4.8, 4.85,
4.9, 4.95, 5.0, 5.05, 5.1, 5.15, 5.2, 5.25, 5.3, 5.35, 5.4, 5.45,
or 5.5 nghr/mL/mg.
[0374] In yet another embodiment, the pharmaceutical composition,
when orally administered to a subject, may produce a plasma profile
characterized by an AUC.sub.(4.3-48) for oxycodone after a single
dose from about 5.0 nghr/mL/mg to about 15.0 nghr/mL/mg, from about
7.5 nghr/mL/mg to about 13.5 nghr/mL/mg, from about 9.0 nghr/mL/mg
to about 12.0 nghr/mL/mg, or from about 9.5 nghr/mL/mg to about
11.5 nghr/mL/mg. In another embodiment, the AUC.sub.(4.3-48) for
oxycodone may be about 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8,
5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1,
7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4,
8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7,
9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8,
10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9,
12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0,
13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1,
14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, or 15.0
nghr/mL/mg.
[0375] In one embodiment, the pharmaceutical composition, when
orally administered to a subject in a fasted state, may produce a
plasma profile characterized by an AUC8-12 hr for oxycodone from
about 3% to about 33% of the AUC0-t, from about 10% to about 27% of
the AUC0-t, or from about 15% to about 22% of the AUC0-t. In
another embodiment, the pharmaceutical composition, when orally
administered to a subject in a fed state, may produce a plasma
profile characterized by an AUC8-12 hr for oxycodone from about 5%
to about 35% of the AUC0-t, from about 12% to about 30% of the
AUC0-t, or from about 15% to about 25% of the AUC0-t.
[0376] In an alternate embodiment, the pharmaceutical composition,
when orally administered to a subject, may provide a mean half-life
of oxycodone that ranges from about 3.5 hours to about 5.5 hours,
or from about 4 hours to about 5 hours. In various embodiments, the
mean half-life of oxycodone may be about 3.8, 4.0, 4.2, 4.4, 4.6,
4.8, 5.0, or 5.2 hours.
[0377] In yet another embodiment, the pharmaceutical composition,
when orally administered to a subject, produces a plasma profile
characterized by an abuse quotient for oxycodone from about 3 to
about 5. In other embodiments, the abuse quotient for oxycodone may
be about 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0,
4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0.
[0378] Moreover, upon oral administration, the pharmaceutical
composition disclosed herein may maintain a therapeutic plasma
concentration of acetaminophen of at least about 2 mg/mL from about
1 hour to about 6 hours after administration. In another
embodiment, the pharmaceutical composition may maintain a
therapeutic plasma concentration of acetaminophen of at least about
2 mg/mL from about 0.75 hour to about 6.5 hours after
administration. In yet another embodiment, the composition may
maintain a plasma concentration of acetaminophen of at least about
1 mg/mL from about 0.5 hour to about 12 hours after
administration.
[0379] In another embodiment, the pharmaceutical composition, when
orally administered to a subject, may produce a plasma profile
characterized by a mean C.sub.max for acetaminophen from about 4.0
ng/mL/mg to about 11.0 ng/mL/mg. In other embodiments, the mean
C.sub.max for acetaminophen may be from about 4.0, 4.5, 5.0, 5.5,
6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, or 11.0
ng/mL/mg. Moreover, the mean C.sub.max for acetaminophen at steady
state may range from about 6.0 ng/mL/mg to about 9.0 ng/mL/mg, from
about 6.5 ng/mL/mg to about 8.5 ng/mL/mg, or from about 7.0
ng/mL/mg to about 8.0 ng/mL/mg.
[0380] In a further embodiment, the pharmaceutical composition,
when orally administered to a subject, surprisingly may produce a
blood plasma concentration profile characterized by a biphasic
increase in blood plasma concentrations of acetaminophen. The
biphasic absorption of acetaminophen may characterized by an
initial rapid absorption resulting in first peak in plasma
concentrations between about 0.5 hour and 2 hours, which
contributes to the early onset on action, and a second peak in
plasma concentrations between about 3 hours and 7 hours after
administration of the composition, which contributes to the
duration or maintenance of analgesia. In some instances, the second
peak may correspond to the overall Cmax of the composition. The
biphasic increase in blood plasma concentrations of acetaminophen
is characterized by a plasma concentration-time profile for
acetaminophen in which the slope of a line drawn between 0 hour and
2 hour is greater than the slope of a line drawn between about 2
hours and 5 hours. See FIG. 24.
[0381] This biphasic increase in acetaminophen levels resulting
from the composition has several benefits. For example, the initial
rapid rise in plasma levels produce quick onset of analgesia and
the slower absorption provides maintenance of analgesia for an
extended period of time.
[0382] In a further embodiment, the pharmaceutical composition,
when orally administered to a subject, may produce a plasma profile
characterized by a mean AUC for acetaminophen from about 35.0
nghr/mL/mg to about 80.0 nghr/mL/mg. In a further embodiment, the
mean AUC for acetaminophen may range from about 35.0 nghr/mL/mg to
about 60.0 nghr/mL/mg. In other embodiments, the mean AUC for
acetaminophen may be about 35.0, 40.0, 45.0, 50.0, 55.0, 60.0,
65.0, 70.0, 75.0, or 80.0 nghr/mL/mg. Additionally, the mean AUC
for acetaminophen at steady state may range from about 40.0
nghr/mL/mg to about 50.0 nghr/mL/mg, from about 35.0 nghr/mL/mg to
about 45.0 nghr/mL/mg, or from about 37.0 nghr/mL/mg to about 42.0
nghr/mL/mg.
[0383] In yet another embodiment, the pharmaceutical composition
when orally administered to a subject, may produce a plasma profile
characterized by a median Tmax for acetaminophen from about 0.5
hours to about 6.0 hours. In another embodiment, the median Tmax
for acetaminophen may be from about 1.0 hour to about 5.0 hours. In
a further embodiment, the median Tmax for acetaminophen may range
from about 0.5 hour to about 4.0 hours. In still another
embodiment, the median Tmax for acetaminophen may range from about
0.75 to about 1.5 hours. In other embodiments, the median Tmax may
be about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5,
1.6, 1.7 1.8, 1.9, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6,
3.8, 4.0, 4.2, 4.4, 4.6, 4.8, or 5.0 hours. Moreover, the median
Tmax for acetaminophen at steady state may range from about 0.5
hour to about 1.0 hour, or from about 0.5 hour to about 0.75
hour.
[0384] In a further embodiment, the pharmaceutical composition,
when orally administered to a subject, may produce a plasma profile
characterized by a median tlag for acetaminophen from about 0 hour
to about 0.5 hour. In an alternate embodiment, the median tlag for
acetaminophen may be from about 0 hour to about 0.25 hour. In one
embodiment, the median tlag for acetaminophen may be 0 hour. In
another embodiment, the median tlag for acetaminophen may be 0.25
hour.
[0385] In one embodiment, the pharmaceutical composition, when
orally administered to a subject, may produce a plasma profile
characterized by various partial AUCs for acetaminophen. The
partial AUCs for acetaminophen are calculated as described above
for oxycodone. The pharmaceutical composition, when orally
administered to a subject, may produce a plasma profile
characterized by an AUC0-1 hr for acetaminophen from about 1.25
nghr/mL/mg to about 3.25 nghr/mL/mg, from about 1.60 nghr/mL/mg to
about 2.0 nghr/mL/mg, or from about 2.0 nghr/mL/mg to about 2.75
nghr/mL/mg. In another embodiment, the AUC0-1 hr for acetaminophen
may be about 1.25, 1.30, 1.40, 1.50, 1.55, 1.60, 1.65, 1.70, 1.75,
1.80, 1.85, 1.90, 1.95, 2.0, 2.05, 2.10, 2.15, 2.20, 2.25, 2.30,
2.35, 2.40, 2.45, 2.50, 2.55, 2.60, 2.65, 2.70, 2.75, 2.80, 2.85,
or 2.90 or nghr/mL/mg.
[0386] In an additional embodiment, the pharmaceutical composition,
when orally administered to a subject, may produce a plasma profile
characterized by an AUC.sub.0-2hr for acetaminophen from about 4.25
nghr/mL/mg to about 14.0 nghr/mL/mg, or from about 5.50 nghr/mL/mg
to about 6.0 nghr/mL/mg, or from about 6.0 nghr/mL/mg to about 7.25
nghr/mL/mg, or from about 7.25 nghr/mL/mg to about 8.5 nghr/mL/mg,
or from about 8.5 nghr/mL/mg to about 9.75 nghr/mL/mg, or from
about 9.75 nghr/mL/mg to about 11.0 nghr/mL/mg, or from about 11.0
nghr/mL/mg to about 12.25 nghr/mL/mg. In another embodiment, the
AUC.sub.0-2hr for acetaminophen may be about 4.25, 4.5, 4.75, 5.0,
5.25, 5.5, 5.75, 6.0, 6.25, 6.5, 6.75, 7.0, 7.25, 7.50, 7.75 8.0,
8.25, 8.5, 8.75, 9.0, 9.25, 9.5, 9.75, 10.0, 10.25, 10.5, 10.75,
11.0, 11.25, 11.5, 11.75, 12.0, 12.25, 12.5, 12.75, 13.0, 13.25,
13.5, 13.75, or 14.0 nghr/mL/mg.
[0387] In an additional embodiment, the pharmaceutical composition,
when orally administered to a subject under fasted conditions, may
produce a plasma profile characterized by an AUC.sub.0-2hr for
acetaminophen from about 7.25 nghr/mL/mg to about 14.0 nghr/mL/mg,
or from about 7.25 nghr/mL/mg to about 8.5 nghr/mL/mg, or from
about 8.5 nghr/mL/mg to about 9.75 nghr/mL/mg, or from about 9.75
nghr/mL/mg to about 11.0 nghr/mL/mg, or from about 11.0 nghr/mL/mg
to about 12.25 nghr/mL/mg. In another embodiment, the AUC.sub.0-2hr
for acetaminophen may be about 7.25, 7.50, 7.75 8.0, 8.25, 8.5,
8.75, 9.0, 9.25, 9.5, 9.75, 10.0, 10.25, 10.5, 10.75, 11.0, 11.25,
11.5, 11.75, 12.0, 12.25, 12.5, 12.75, 13.0, 13.25, 13.5, 13.75, or
14.0 nghr/mL/mg.
[0388] In an additional embodiment, the pharmaceutical composition,
when orally administered to a subject under fed conditions (high
fat meal), may produce a plasma profile characterized by an
AUC.sub.0-2hr for acetaminophen from about 4.5 nghr/mL/mg to about
8.75 nghr/mL/mg, or from about 5.0 nghr/mL/mg to about 6.0
nghr/mL/mg, or from about 6.0 nghr/mL/mg to about 7.0 nghr/mL/mg,
or from about 7.0 nghr/mL/mg to about 8.0 nghr/mL/mg. In another
embodiment, the AUC.sub.0-2hr for acetaminophen may be about 4.5,
4.75, 5.0, 5.25, 5.5, 5.75, 6.0, 6.25, 6.5, 6.75, 7.0, 7.25, 7.50,
7.75 8.0, 8.25, 8.5, or 8.75 nghr/mL/mg.
[0389] In an additional embodiment, the pharmaceutical composition,
when orally administered to a subject under fed conditions (low fat
meal), may produce a plasma profile characterized by an
AUC.sub.0-2hr for acetaminophen from about 4.5 nghr/mL/mg to about
8.75 nghr/mL/mg, or from about 5.0 nghr/mL/mg to about 6.0
nghr/mL/mg, or from about 6.0 nghr/mL/mg to about 7.0 nghr/mL/mg,
or from about 7.0 nghr/mL/mg to about 8.0 nghr/mL/mg. In another
embodiment, the AUC.sub.0-2hr for acetaminophen may be about 4.5,
4.75, 5.0, 5.25, 5.5, 5.75, 6.0, 6.25, 6.5, 6.75, 7.0, 7.25, 7.50,
7.75 8.0, 8.25, 8.5, or 8.75 nghr/mL/mg.
[0390] In an additional embodiment, the pharmaceutical composition,
when orally administered to a subject, may produce a plasma profile
characterized by an AUC.sub.2-48hr for acetaminophen from about
26.0 nghr/mL/mg to about 53.5 nghr/mL/mg, or from about 32.0
nghr/mL/mg to about 35.0 nghr/mL/mg, or from about 35.0 nghr/mL/mg
to about 38.0 nghr/mL/mg, or from about 38.0 nghr/mL/mg to about
41.0 nghr/mL/mg, or from about 41.0 nghr/mL/mg to about 44.0
nghr/mL/mg, or from about 44.0 nghr/mL/mg to about 47.0 nghr/mL/mg,
or from about 47.0 nghr/mL/mg to about 50.0 nghr/mL/mg. In another
embodiment, the AUC.sub.2-48hr for acetaminophen may be about 26.0,
26.5, 27.0, 27.5, 28.0, 28.5, 29.0, 29.5, 30.0, 30.5, 31.0, 31.5,
32.0, 32.5, 33.0, 33.5, 34.0, 34.5, 35.0, 35.5, 36.0, 36.5, 37.0,
37.5, 38.0, 38.5, 39.0, 39.5, 40.0, 40.5, 41.0, 41.5, 42.0, 42.5,
43.0, 43.5, 44.0, 44.5, 45.0, 45.5, 46.0, 46.5, 47.0, 47.5, 48.0,
48.5, 49.0, 49.5, 50.0, 50.5, 51.0, 51.5, 52.0, 52.5, 53.0, or 53.5
nghr/mL/mg.
[0391] In an additional embodiment, the pharmaceutical composition,
when orally administered to a subject under fasted conditions, may
produce a plasma profile characterized by an AUC.sub.2-48hr for
acetaminophen from about 26.0 nghr/mL/mg to about 49.0 nghr/mL/mg,
or from about 32.0 nghr/mL/mg to about 35.0 nghr/mL/mg, or from
about 35.0 nghr/mL/mg to about 38.0 nghr/mL/mg, or from about 38.0
nghr/mL/mg to about 41.0 nghr/mL/mg, or from about 41.0 nghr/mL/mg
to about 44.0 nghr/mL/mg, or from about 44.0 nghr/mL/mg to about
47.0 nghr/mL/mg. In another embodiment, the AUC.sub.2-48hr for
acetaminophen may be about 26.0, 26.5, 27.0, 27.5, 28.0, 28.5,
29.0, 29.5, 30.0, 30.5, 31.0, 31.5, 32.0, 32.5, 33.0, 33.5, 34.0,
34.5, 35.0, 35.5, 36.0, 36.5, 37.0, 37.5, 38.0, 38.5, 39.0, 39.5,
40.0, 40.5, 41.0, 41.5, 42.0, 42.5, 43.0, 43.5, 44.0, 44.5, 45.0,
45.5, 46.0, 46.5, 47.0, 47.5, 48.0, 48.5, or 49.0.
[0392] In an additional embodiment, the pharmaceutical composition,
when orally administered to a subject under fed conditions (high
fat meal), may produce a plasma profile characterized by an
AUC.sub.2-48hr for acetaminophen from about 28.5 nghr/mL/mg to
about 53.5 nghr/mL/mg, or from about 32.0 nghr/mL/mg to about 35.0
nghr/mL/mg, or from about 35.0 nghr/mL/mg to about 38.0 nghr/mL/mg,
or from about 38.0 nghr/mL/mg to about 41.0 nghr/mL/mg, or from
about 41.0 nghr/mL/mg to about 44.0 nghr/mL/mg, or from about 44.0
nghr/mL/mg to about 47.0 nghr/mL/mg, or from about 47.0 nghr/mL/mg
to about 50.0 nghr/mL/mg. In another embodiment, the AUC.sub.2-48hr
for acetaminophen may be about 28.5, 29.0, 29.5, 30.0, 30.5, 31.0,
31.5, 32.0, 32.5, 33.0, 33.5, 34.0, 34.5, 35.0, 35.5, 36.0, 36.5,
37.0, 37.5, 38.0, 38.5, 39.0, 39.5, 40.0, 40.5, 41.0, 41.5, 42.0,
42.5, 43.0, 43.5, 44.0, 44.5, 45.0, 45.5, 46.0, 46.5, 47.0, 47.5,
48.0, 48.5, 49.0, 49.5, 50.0, 50.5, 51.0, 51.5, 52.0, 52.5, 53.0,
or 53.5 nghr/mL/mg.
[0393] In an additional embodiment, the pharmaceutical composition,
when orally administered to a subject under fed conditions (low fat
meal), may produce a plasma profile characterized by an
AUC.sub.2-48hr for acetaminophen from about 28.0 nghr/mL/mg to
about 52.5 nghr/mL/mg, or from about 32.0 nghr/mL/mg to about 35.0
nghr/mL/mg, or from about 35.0 nghr/mL/mg to about 38.0 nghr/mL/mg,
or from about 38.0 nghr/mL/mg to about 41.0 nghr/mL/mg, or from
about 41.0 nghr/mL/mg to about 44.0 nghr/mL/mg, or from about 44.0
nghr/mL/mg to about 47.0 nghr/mL/mg, or from about 47.0 nghr/mL/mg
to about 50.0 nghr/mL/mg. In another embodiment, the AUC.sub.2-48hr
for acetaminophen may be about 28.0, 28.5, 29.0, 29.5, 30.0, 30.5,
31.0, 31.5, 32.0, 32.5, 33.0, 33.5, 34.0, 34.5, 35.0, 35.5, 36.0,
36.5, 37.0, 37.5, 38.0, 38.5, 39.0, 39.5, 40.0, 40.5, 41.0, 41.5,
42.0, 42.5, 43.0, 43.5, 44.0, 44.5, 45.0, 45.5, 46.0, 46.5, 47.0,
47.5, 48.0, 48.5, 49.0, 49.5, 50.0, 50.5, 51.0, 51.5, 52.0, or 52.5
nghr/mL/mg.
[0394] In an additional embodiment, the pharmaceutical composition,
when orally administered to a subject, may produce a plasma profile
characterized by an AUC.sub.8-10hr for acetaminophen from about 2.3
nghr/mL/mg to about 6.0 nghr/mL/mg, or from about 2.50 nghr/mL/mg
to about 3.0 nghr/mL/mg, or from about 3.0 nghr/mL/mg to about 3.5
nghr/mL/mg, or from about 3.5 nghr/mL/mg to about 4.0 nghr/mL/mg,
or from about 4.0 nghr/mL/mg to about 4.5 nghr/mL/mg, or from about
4.5 nghr/mL/mg to about 5.0 nghr/mL/mg, or from about 5.0
nghr/mL/mg to about 5.5 nghr/mL/mg. In another embodiment, the
AUC.sub.8-10hr for acetaminophen may be about 2.3, 2.4, 2.5, 2.6,
2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9,
4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2,
5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, or 6.0 nghr/mL/mg.
[0395] In an additional embodiment, the pharmaceutical composition,
when orally administered to a subject under fasted conditions, may
produce a plasma profile characterized by an AUC.sub.8-10hr for
acetaminophen from about 2.3 nghr/mL/mg to about 4.5 nghr/mL/mg, or
from about 2.50 nghr/mL/mg to about 3.0 nghr/mL/mg, or from about
3.0 nghr/mL/mg to about 3.5 nghr/mL/mg, or from about 3.5
nghr/mL/mg to about 4.0 nghr/mL/mg. In another embodiment, the
AUC.sub.8-10hr for acetaminophen may be about 2.3, 2.4, 2.5, 2.6,
2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9,
4.0, 4.1, 4.2, 4.3, 4.4, or 4.5 nghr/mL/mg.
[0396] In an additional embodiment, the pharmaceutical composition,
when orally administered to a subject under fed conditions (high
fat meal), may produce a plasma profile characterized by an
AUC.sub.8-10hr for acetaminophen from about 3.0 nghr/mL/mg to about
5.8 nghr/mL/mg, or from about 3.5 nghr/mL/mg to about 4.0
nghr/mL/mg, or from about 4.0 nghr/mL/mg to about 4.5 nghr/mL/mg,
or from about 4.5 nghr/mL/mg to about 5.0 nghr/mL/mg, or from about
5.0 nghr/mL/mg to about 5.5 nghr/mL/mg. In another embodiment, the
AUC.sub.8-10hr for acetaminophen may be about 3.0, 3.1, 3.2, 3.3,
3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6,
4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, or 5.8
nghr/mL/mg.
[0397] In an additional embodiment, the pharmaceutical composition,
when orally administered to a subject under fed conditions (low fat
meal), may produce a plasma profile characterized by an
AUC.sub.8-10hr for acetaminophen from about 3.0 nghr/mL/mg to about
6.0 nghr/mL/mg, or from about 3.5 nghr/mL/mg to about 4.0
nghr/mL/mg, or from about 4.0 nghr/mL/mg to about 4.5 nghr/mL/mg,
or from about 4.5 nghr/mL/mg to about 5.0 nghr/mL/mg, or from about
5.0 nghr/mL/mg to about 5.5 nghr/mL/mg. In another embodiment, the
AUC.sub.8-10hr for acetaminophen may be about 3.0, 3.1, 3.2, 3.3,
3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6,
4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, or
6.0 nghr/mL/mg.
[0398] In an additional embodiment, the pharmaceutical composition,
when orally administered to a subject, may produce a plasma profile
characterized by an AUC.sub.10-12hr for acetaminophen from about
1.8 nghr/mL/mg to about 5.0 nghr/mL/mg, or from about 2.0
nghr/mL/mg to about 2.5 nghr/mL/mg, or from about 2.5 nghr/mL/mg to
about 3.0 nghr/mL/mg, or from about 3.0 nghr/mL/mg to about 3.5
nghr/mL/mg, or from about 3.5 nghr/mL/mg to about 4.0 nghr/mL/mg,
or from about 4.0 nghr/mL/mg to about 4.5 nghr/mL/mg. In another
embodiment, the AUC.sub.10-12hr for acetaminophen may be about 1.8.
1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1,
3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4,
4.5, 4.6, 4.7, 4.8, 4.9, or 5.0 nghr/mL/mg.
[0399] In an additional embodiment, the pharmaceutical composition,
when orally administered to a subject under fasted conditions, may
produce a plasma profile characterized by an AUC.sub.10-12hr for
acetaminophen from about 1.8 nghr/mL/mg to about 3.5 nghr/mL/mg, or
from about 2.0 nghr/mL/mg to about 2.5 nghr/mL/mg, or from about
2.5 nghr/mL/mg to about 3.0 nghr/mL/mg, or from about 3.0
nghr/mL/mg to about 3.5 nghr/mL/mg. In another embodiment, the
AUC.sub.10-12hr for acetaminophen may be about 1.8. 1.9, 2.0, 2.1,
2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, or
3.5 nghr/mL/mg.
[0400] In an additional embodiment, the pharmaceutical composition,
when orally administered to a subject under fed conditions (high
fat meal), may produce a plasma profile characterized by an
AUC.sub.10-12hr for acetaminophen from about 2.7 nghr/mL/mg to
about 5.0 nghr/mL/mg, or from about 3.0 nghr/mL/mg to about 3.5
nghr/mL/mg, or from about 3.5 nghr/mL/mg to about 4.0 nghr/mL/mg,
or from about 4.0 nghr/mL/mg to about 4.5 nghr/mL/mg. In another
embodiment, the AUC.sub.10-12hr for acetaminophen may be about 2.7,
2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0,
4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0 nghr/mL/mg.
[0401] In an additional embodiment, the pharmaceutical composition,
when orally administered to a subject under fed conditions (low fat
meal), may produce a plasma profile characterized by an
AUC.sub.10-12hr for acetaminophen from about 2.4 nghr/mL/mg to
about 4.5 nghr/mL/mg, or from about 2.5 nghr/mL/mg to about 3.0, or
from about 3.0 nghr/mL/mg to about 3.5 nghr/mL/mg, or from about
3.5 nghr/mL/mg to about 4.0 nghr/mL/mg, or from about 4.0
nghr/mL/mg to about 4.5 nghr/mL/mg. In another embodiment, the
AUC.sub.10-12hr for acetaminophen may be about 2.4, 2.5, 2.6, 2.7,
2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0,
4.1, 4.2, 4.3, 4.4, or 4.5 nghr/mL/mg.
[0402] In a further embodiment, the pharmaceutical composition,
when orally administered to a subject, may produce a plasma profile
characterized by an AUC.sub.0-4hr for acetaminophen from about 10.0
nghr/mL/mg to about 20.0 nghr/mL/mg, from about 13.0 nghr/mL/mg to
about 14.5 nghr/mL/mg, or from about 14.5 nghr/mL/mg to about 16.5
nghr/mL/mg. In another embodiment, the AUC.sub.0-4 hr for
acetaminophen may be about 10.0, 11.0, 12.0, 13.0, 13.5, 14.0,
14.5, 15.0, 15.5, 16.0, 16.5, or 17.0 nghr/mL/mg.
[0403] In yet another embodiment, the pharmaceutical composition,
when orally administered to a subject, may produce a plasma profile
characterized by an AUC.sub.Tmax-t for acetaminophen from about
20.0 nghr/mL/mg to about 40.0 nghr/mL/mg, from about 23.5
nghr/mL/mg to about 36.0 nghr/mL/mg, or from about 29.0 nghr/mL/mg
to about 31.0 nghr/mL/mg. In another embodiment, the AUC.sub.Tmax-t
for acetaminophen may be about 20.0, 21.0, 22.0, 23.0, 23.5, 24.0,
24.5, 25.0, 25.5, 26.0, 26.5, 27.0, 27.5, 28.0, 28.5, 29.0, 29.5,
30.0, 30.5, 31.0, 31.5, 32.0, 32.5, 33.0, 33.5, 34.0, 34.5, 35.0,
35.5 or 36.0 nghr/mL/mg.
[0404] In yet another embodiment, the pharmaceutical composition,
when orally administered to a subject, may produce a plasma profile
characterized by an AUC(0-(Tmax of IR product+2SD)) for
acetaminophen after a single dose from about 5.0 nghr/mL/mg to
about 13.0 nghr/mL/mg, from about 7.2 nghr/mL/mg to about 11.6
nghr/mL/mg, or from about 8.5 nghr/mL/mg to about 10.0 nghr/mL/mg.
In another embodiment, the AUC(0-(Tmax of IR product+2SD)) for
acetaminophen may be about 5.0, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6,
6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9,
8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2,
9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4,
10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5,
11.6, 11.7, 11.8, 11.9, or 12.0 nghr/mL/mg.
[0405] In one embodiment, the immediate release product referenced
for the Partial AUC calculations is Percocet in the fasted state
and the following calculation was used to determine AUC(0-(Tmax of
IR product+2SD)):
acetaminophen mean.+-.SD=0.596 h.+-.0.529 h; Tmax+2SD=1.65 hour
In such embodiment, the pharmaceutical composition, when orally
administered to a subject, may produce a plasma profile
characterized by an AUC(0-1.7) for acetaminophen after a single
dose from about 5.0 nghr/mL/mg to about 13.0 nghr/mL/mg, from about
7.2 nghr/mL/mg to about 11.6 nghr/mL/mg, or from about 8.5
nghr/mL/mg to about 10.0 nghr/mL/mg. In another embodiment, the
AUC(0-1.7) for acetaminophen may be about 5.0, 5.1, 5.2, 5.3, 5.4,
5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7,
6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0,
8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3,
9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5,
10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6,
11.7, 11.8, 11.9, or 12.0 nghr/mL/mg.
[0406] In still a further embodiment, the pharmaceutical
composition, when orally administered to a subject, may produce a
plasma profile characterized by an AUC(1.7-48) for acetaminophen
after a single dose from about 25.0 nghr/mL/mg to about 75.0
nghr/mL/mg, from about 31.5 nghr/mL/mg to about 55.0 nghr/mL/mg, or
from about 35.0 nghr/mL/mg to about 50.0 nghr/mL/mg. In another
embodiment, the AUC(1.7-48) for acetaminophen may be about 25.0,
25.5, 26.0, 26.5, 27.0, 27.5, 28.0, 28.5, 29.0, 29.5, 30.0, 30.5,
31.0, 31.5, 32.0, 32.5, 33.0, 33.5, 34.0, 34.5, 35.0, 35.5, 36.0,
36.5, 37.0, 37.5, 38.0, 38.5, 39.0, 39.5, 40.0, 40.5, 41.0, 41.5,
42.0, 42.5, 43.0, 43.5, 44.0, 44.5, 45.0, 45.5, 46.0, 46.5, 47.0,
47.5, 48.0, 48.5, 49.0, 49.5, 50.0, 50.5, 51.0, 51.5, 52.0, 52.5,
53.0, 53.5, 54.0, 54.5, or 55.0 nghr/mL/mg.
[0407] In one embodiment, the immediate release product referenced
for the Partial AUC calculations is Percocet in the fed state and
the following calculation was used to determine AUC(0-(Tmax of IR
product+2SD)):
acetaminophen mean.+-.SD=1.48 h.+-.0.875 h; Tmax+2SD=3.2 hour
In such embodiment, the pharmaceutical composition, when orally
administered to a subject, may produce a plasma profile
characterized by an AUC(0-3.2) for acetaminophen after a single
dose from about 7.0 nghr/mL/mg to about 21.0 nghr/mL/mg, from about
9.0 nghr/mL/mg to about 18.0 nghr/mL/mg, from about 10.0 nghr/mL/mg
to about 16.0 nghr/mL/mg, or from about 12.0 nghr/mL/mg to about
15.0 nghr/mL/mg. In another embodiment, the AUC(0-3.2) for
acetaminophen may be about 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7,
7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0,
9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2,
10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3,
11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4,
12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5,
13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6,
14.7, 14.8, 14.9, 15.0, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7,
15.8, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8,
16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9,
18.0, 18.1, 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19.0,
19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.0, 20.1,
20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, or 21.0
nghr/mL/mg.
[0408] In still a further embodiment, the pharmaceutical
composition, when orally administered to a subject, may produce a
plasma profile characterized by an AUC(3.2-48) for acetaminophen
after a single dose from about 15.0 nghr/mL/mg to about 75.0
nghr/mL/mg, from about 25.0 nghr/mL/mg to about 55.0 nghr/mL/mg,
from about 27.5 nghr/mL/mg to about 45.0 nghr/mL/mg, or from about
30.0 nghr/mL/mg to about 40.0 nghr/mL/mg. In another embodiment,
the AUC(3.2-48) for acetaminophen may be about 15.0, 15.5, 16.0,
16.5, 17.0, 17.5, 18.0, 18.5, 19.0, 19.5, 20.0, 20.5, 21.0, 21.5,
22.0, 22.5, 23.0, 23.5, 24.0, 24.5, 25.0, 25.5, 26.0, 26.5, 27.0,
27.5, 28.0, 28.5, 29.0, 29.5, 30.0, 30.5, 31.0, 31.5, 32.0, 32.5,
33.0, 33.5, 34.0, 34.5, 35.0, 35.5, 36.0, 36.5, 37.0, 37.5, 38.0,
38.5, 39.0, 39.5, 40.0, 40.5, 41.0, 41.5, 42.0, 42.5, 43.0, 43.5,
44.0, 44.5, 45.0, 45.5, 46.0, 46.5, 47.0, 47.5, 48.0, 48.5, 49.0,
49.5, 50.0, 50.5, 51.0, 51.5, 52.0, 52.5, 53.0, 53.5, 54.0, 54.5,
55.0, 55.5, 56.0, 56.5, 57.0, 57.5, 58.0, 58.5, 59.0, 59.5, 60.0,
60.5, 61.0, 61.5, 62.0, 62.5, 63.0, 63.5, 64.0, 64.5, 65.0, 65.5,
66.0, 66.5, 67.0, 67.5, 68.0, 68.5, 69.0, 69.5, 70.0, 70.5, 71.0,
71.5, 72.0, 72.5, 73.0, 73.5, 74.0, 74.5, or 75.0 nghr/mL/mg.
[0409] In one embodiment, the pharmaceutical composition, when
orally administered to a subject, may produce a plasma profile
characterized by an AUC0-12 hr for acetaminophen from about 20.0
nghr/mL/mg to about 60.0 nghr/mL/mg, from about 30 nghr/mL/mg to
about 50 nghr/mL/mg, from about 35 to about 45 nghr/mL/mg, or from
about 37.5 nghr/mL/mg to about 42.5 nghr/mL/mg. In another
embodiment, the pharmaceutical composition, when orally
administered to a subject, may produce a plasma profile
characterized by an AUC0-12 hr for acetaminophen from about 20.0,
20.5, 21.0, 21.5, 22.0, 22.5, 23.0, 23.5, 24.0, 24.5, 25.0, 25.5,
26.0, 26.5, 27.0, 27.5, 28.0, 28.5, 29.0, 29.5, 30.0, 30.5, 31.0,
31.5, 32.0, 32.5, 33.0, 33.5, 34.0, 34.5, 35.0, 35.5, 36.0, 36.5,
37.0, 37.5, 38.0, 38.5, 39.0, 39.5, 40.0, 40.5, 41.0, 41.5, 42.0,
42.5, 43.0, 43.5, 44.0, 44.5, 45.0, 45.5, 46.0, 46.5, 47.0, 47.5,
48.0, 48.5, 49.0, 49.5, 50.0, 50.5, 51.0, 51.5, 52.0, 52.5, 53.0,
53.5, 54.0, 54.5, or 55.0. In a further embodiment, at AUC0-12 hr
between about 70%-95%, about 75%-92%, or about 77%-90% of the
acetaminophen has been cleared. In still another embodiment, about
80% of the acetaminophen has been cleared.
[0410] In another embodiment, the pharmaceutical composition, when
orally administered to a subject, may produce a plasma profile
characterized by an AUC1-12 hr for acetaminophen from about 15.0
nghr/mL/mg to about 55.0 nghr/mL/mg, from about 25.0 nghr/mL/mg to
about 45.0 nghr/mL/mg, or from about 30.0 to about 40.0 nghr/mL/mg.
In another embodiment, the pharmaceutical composition, when orally
administered to a subject, may produce a plasma profile
characterized by an AUC1-12 hr for acetaminophen from about 15, 16,
17, 18, 19, 20.0, 20.5, 21.0, 21.5, 22.0, 22.5, 23.0, 23.5, 24.0,
24.5, 25.0, 25.5, 26.0, 26.5, 27.0, 27.5, 28.0, 28.5, 29.0, 29.5,
30.0, 30.5, 31.0, 31.5, 32.0, 32.5, 33.0, 33.5, 34.0, 34.5, 35.0,
35.5, 36.0, 36.5, 37.0, 37.5, 38.0, 38.5, 39.0, 39.5, 40.0, 40.5,
41.0, 41.5, 42.0, 42.5, 43.0, 43.5, 44.0, 44.5, 45.0, 45.5, 46.0,
46.5, 47.0, 47.5, 48.0, 48.5, 49.0, 49.5, or 50.0 nghr/mL/mg.
[0411] In yet another embodiment, the pharmaceutical composition,
when orally administered to a subject, may produce a plasma profile
characterized by an AUC12-36 hr for acetaminophen from about 5.0
nghr/mL/mg to about 25.0 nghr/mL/mg, from about 7.5 nghr/mL/mg to
about 20.0 nghr/mL/mg, or from about 10.0 nghr/mL/mg to about 15.0.
In other embodiments, the pharmaceutical composition, when orally
administered to a subject, may produce a plasma profile
characterized by an AUC12-36 hr for acetaminophen from about 5.0,
6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2,
7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5,
8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8,
9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9,
11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0,
12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1,
13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2,
14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, or 15.0 nghr/mL/mg.
[0412] In another embodiment, the pharmaceutical composition, when
orally administered to a subject, may produce a plasma profile
characterized by an AUC8-12 hr for acetaminophen from about 1.5
nghr/mL/mg to about 15.5 nghr/mL/mg, from about 2 nghr/mL/mg to
about 12.25 nghr/mL/mg, from about 3.5 nghr/mL/mg to about 10
nghr/mL/mg, or from about 4.5 nghr/mL/mg to about 6.5 nghr/mL/mg.
In other embodiments, the pharmaceutical composition, when orally
administered to a subject, may produce a plasma profile
characterized by an AUC8-12 hr for acetaminophen from about 1.5,
1.75, 2.0, 2.25, 2.5, 2.75, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7,
3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0,
5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3,
6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6,
7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9,
9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2,
10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3,
11.4, 11.5, 11.6, 11.7, 11.8, 11.9, or 12.0 nghr/mL/mg.
[0413] In one embodiment, the pharmaceutical composition, when
orally administered to a subject, may produce a plasma profile
characterized by an AUC(0-3 hr) for acetaminophen from about 5
nghr/mL/mg to about 30 nghr/mL/mg, from about 10 nghr/mL/mg to
about 20 nghr/mL/mg, or from about 13 nghr/mL/mg to about 17
nghr/mL/mg. In other embodiments, the pharmaceutical composition,
when orally administered to a subject, may produce a plasma profile
characterized by an AUC(0-3 hr) for acetaminophen from about 5.0,
6.0, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1,
8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4,
9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6,
10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7,
11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8,
12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9,
14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0,
15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16.0, 16.1,
16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2,
17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18.0, 18.1, 18.2, 18.3,
18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1, 19.2, 19.3, 19.4,
19.5, 19.6, 19.7, 19.8, 19.9, or 20.0 nghr/mL/mg.
[0414] In another embodiment, the pharmaceutical composition, when
orally administered to a subject, may produce a plasma profile
characterized by an AUC(3-36 hr) for acetaminophen from about 20
nghr/mL/mg to about 50 nghr/mL/mg, from about 20 nghr/mL/mg to
about 40 nghr/mL/mg, or from about 25 nghr/mL/mg to about 35
nghr/mL/mg. In other embodiments, the pharmaceutical composition,
when orally administered to a subject, may produce a plasma profile
characterized by an AUC(3-36 hr) for acetaminophen from about 20,
20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5,
27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 31.5, 32, 32.5, 33,
33.5, 34, 34.5, 35, 35.5, 36, 36.5, 37, 37.5, 38, 38.5, 39, 39.5,
40, 40.5, 41, 41.5, 42, 42.5, 43, 43.5, 44, 44.5, 45, 45.5, 46,
46.5, 47, 47.5, 48, 48.5, 49, 49.5, or 50 nghr/mL/mg.
[0415] In one embodiment, the pharmaceutical composition, when
orally administered to a subject, may produce a plasma profile
characterized by an AUC0-12 hr for acetaminophen from about 50% to
about 90% of the AUC0-t, from about 55% to about 85% of the AUC0-t,
or from about 75% to about 85% of the AUC0-t. In other embodiments,
the pharmaceutical composition, when orally administered to a
subject, may produce a plasma profile characterized by an AUC0-12
hr for acetaminophen that is about 50%, 55%, 60%, 65%, 70%, 75%,
76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84% or 85% of the
AUC0-t.
[0416] In one embodiment, the pharmaceutical composition, when
orally administered to a subject, may produce a plasma profile
characterized by an AUC1-12 hr for acetaminophen from about 40% to
about 90% of the AUC0-t, from about 55% to about 85% of the AUC0-t,
or from about 60% to about 75% of the AUC0-t. In other embodiments,
the pharmaceutical composition, when orally administered to a
subject, may produce a plasma profile characterized by an AUC1-12
hr for acetaminophen of about 40%, 45%, 50%, 55%, 60%, 61%, 62%,
63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%,
76%, 77%, 78%, 79%, or 80% of the AUC0-t.
[0417] In one embodiment, the pharmaceutical composition, when
orally administered to a subject, may produce a plasma profile
characterized by an AUC12-36 hr for acetaminophen from about 10% to
about 40% of the AUC0-t, from about 15% to about 35% of the AUC0-t,
or from about 20% to about 30% of the AUC0-t. In other embodiments,
the pharmaceutical composition, when orally administered to a
subject, may produce a plasma profile characterized by an AUC12-36
hr for acetaminophen of about 10%, 12%, 14%, 16%, 18%, 20%, 21%,
22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% of the AUC0-t.
[0418] In one embodiment, the pharmaceutical composition, when
orally administered to a subject, may produce a plasma profile
characterized by an AUC8-12 hr for acetaminophen from about 5% to
about 30% of the AUC0-t, from about 7% to about 25% of the AUC0-t,
or from about 10% to about 20% of the AUC0-t. In other embodiments,
the pharmaceutical composition, when orally administered to a
subject, may produce a plasma profile characterized by an AUC8-12
hr for acetaminophen of about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%,
13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25%
of the AUC0-t.
[0419] In an alternate embodiment, the pharmaceutical composition,
when orally administered to a subject, may have a mean half-life of
acetaminophen that ranges from about 2 hours to about 10 hours, or
from about 3 hours to about 6 hours. In another embodiment, the
pharmaceutical composition, when orally administered to a subject,
may have a mean half-life of acetaminophen that ranges from about 3
hours to about 5 hours. In still another embodiment, the
pharmaceutical composition, when orally administered to a subject,
may have a mean half-life of acetaminophen that ranges from about 4
hours to about 5 hours. In various embodiments, the mean half-life
of acetaminophen may be about 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5,
6.0, 6.5, 6.0, 7.0, 7.5, or 8 hours. In additional embodiments, the
pharmaceutical composition, when orally administered to a subject,
has a mean observed half-life of acetaminophen that is more than
the mean half-life of commercially available immediate release
acetaminophen products.
[0420] In another embodiment, upon administration of the
pharmaceutical composition to a subject, the composition may
provide at least about 4 hours to about 12 hours of drug delivery
to the upper gastrointestinal tract, which includes the duodenum,
jejunum, and ileum of the small intestine. In another embodiment,
the composition may provide at least about 6 hours of drug delivery
to the upper gastrointestinal tract. In yet a further embodiment,
the composition may provide at least about 8 hours of drug delivery
to the upper gastrointestinal tract. In yet a further embodiment,
the composition may provide at least about 9 hours, or at least
about 10 hours of drug delivery to the upper gastrointestinal
tract.
[0421] In yet another embodiment, upon administration of the
pharmaceutical composition to a subject, APAP undergoes presystemic
metabolism in the gut and/or liver allowing only a fraction of the
drug to reach the systemic circulation. The fraction of drug that
is originally absorbed prior to pre-systemic metabolism is referred
to as the fraction absorbed and denoted "Fab." This is different
from the fraction bioavailable "F," which is the fraction that
reaches the systemic circulation after the metabolism in the gut
and liver.
[0422] In another embodiment, 60-90% of the acetaminophen in the
pharmaceutical composition, which is available for absorption into
the systemic circulation, is absorbed in the upper gastrointestinal
tract. In still another embodiment, 60-85% of acetaminophen in the
pharmaceutical composition, which is available for absorption into
the systemic circulation, is absorbed in the duodenum and jejunum.
See FIG. 27. Greater than 50% absorption of acetaminophen in the
upper gastrointestinal tract is beneficial to a human subject
because acetaminophen is poorly absorbed in the stomach and well
absorbed in the small intestine and particularly, the upper segment
of the gastrointestinal tract. It is therefore critical that
acetaminophen is available in upper small intestine for its
absorption. In one embodiment acetaminophen is released in stomach
and reaches quickly into upper part of the small intestine for the
absorption to take place.
[0423] In another embodiment, when about 60% to about 75% of the
acetaminophen is released from the dosage form in the stomach
within 2 hours following oral administration, about 10% to about
25% of the total amount of the acetaminophen in the dosage form,
which is available for absorption into the systemic circulation, is
absorbed in the duodenum, about 25% to about 40% is absorbed in the
proximal jejunum (noted as "jejunum 1" in FIG. 27), about 15% to
about 20% is absorbed in the distal jejunum (noted as "jejunum 2"
in FIG. 27), and about 5% to about 15% is absorbed in the
ileum.
[0424] In another embodiment, when about 70% to about 90% of the
acetaminophen is released from the dosage form in the stomach
within 4 hours following oral administration, about 10% to about
25% of the total amount of the acetaminophen in the dosage form,
which is available for absorption into the systemic circulation, is
absorbed in the duodenum, about 25% to about 40% is absorbed in the
proximal jejunum (noted as "jejunum 1" in FIG. 27), about 15% to
about 20% is absorbed in the distal jejunum (noted as "jejunum 2"
in FIG. 27), and about 5% to about 15% is absorbed in the
ileum.
[0425] In yet another embodiment, when at least about 55% of the
total amount of the acetaminophen is released from the dosage form
in the stomach within 1 hour after oral administration and when at
least about 60% of the acetaminophen is released in the stomach
after 2 hours, about 15% to about 20% of the total amount of the
acetaminophen in the dosage form, which is available for absorption
into the systemic circulation, is absorbed in the duodenum, about
30% to about 37% is absorbed in the proximal jejunum, about 15% to
about 18% is absorbed in the distal jejunum, and about 8% to about
10% is absorbed in the ileum.
[0426] In still another embodiment, upon administration of the
pharmaceutical composition to a subject, the opioid undergoes
presystemic metabolism in the gut and/or liver allowing only a
fraction of the drug to reach the systemic circulation. The
fraction of drug that is originally absorbed prior to pre-systemic
metabolism is referred to as the fraction absorbed and denoted
"Fab." In one embodiment, the opioid is oxycodone. This is
different from the fraction bioavailable "F," which is the fraction
that reaches the systemic circulation after metabolism in the gut
and liver.
[0427] In a further embodiment, 70-95% of the oxycodone in the
pharmaceutical composition, which is available for absorption into
the systemic circulation, is absorbed in the upper gastrointestinal
tract. In still another embodiment, 80-95% of oxycodone in the
pharmaceutical composition, which is available for absorption into
the systemic circulation, is absorbed in the duodenum and jejunum.
See FIG. 28.
[0428] In one embodiment, the composition releases the opioid and
other API in the stomach to optimize drug absorption in the
duodenum and jejunum. For example, when about 25% to about 50% of
oxycodone is released from the dosage form in the stomach within 1
hour following oral administration, about 10% to about 45% of the
total amount of the oxycodone in the dosage form, which is
available for absorption into the systemic circulation, is absorbed
in the duodenum, about 25% to about 50% is absorbed in the proximal
jejunum (noted as "jejunum 1" in FIG. 28), about 7% to about 20% is
absorbed in the distal jejunum (noted as "jejunum 2" in FIG. 28),
and about 2% to about 15% is absorbed in the ileum.
[0429] In another embodiment, when about 45% to about 65% of
oxycodone is released from the dosage form in the stomach within 2
hours following oral administration, about 10% to about 50% of the
total amount of the oxycodone in the dosage form, which is
available for absorption into the systemic circulation, is absorbed
in the duodenum, about 25% to about 55% is absorbed in the proximal
jejunum (noted as "jejunum 1" in FIG. 28), about 5% to about 25% is
absorbed in the distal jejunum (noted as "jejunum 2" in FIG. 28),
and about 2% to about 15% is absorbed in the ileum.
[0430] In another embodiment, when about 60% to about 85% of
oxycodone is released from the dosage form in the stomach within 4
hours following oral administration, about 10% to about 55% of the
total amount of the oxycodone in the dosage form, which is
available for absorption into the systemic circulation, is absorbed
in the duodenum, about 30% to about 60% is absorbed in the proximal
jejunum (noted as "jejunum 1" in FIG. 28), about 10% to about 30%
is absorbed in the distal jejunum (noted as "jejunum 2" in FIG.
28), and about 2% to about 20% is absorbed in the ileum.
[0431] In yet another embodiment, when at least 25% of the total
amount of the oxycodone is released from the dosage form in the
stomach within 1 hour after oral administration and when at least
45% of the oxycodone is released in the stomach after 2 hours,
about 30% to about 45% of the total amount of oxycodone in the
dosage form, which is available for absorption into the systemic
circulation, is absorbed in the duodenum, about 37% to about 43% is
absorbed in the proximal jejunum (noted as "jejunum 1" in FIG. 28),
about 10% to about 15% is absorbed in the distal jejunum (noted as
"jejunum 2" in FIG. 28), and about 2% to about 8% is absorbed in
the ileum.
[0432] In another embodiment, about 90% to about 100% of the IR
dose of acetaminophen is released within about 15 minutes, 30
minutes, 45 minutes or 60 minutes after oral administration. In one
embodiment, the dosage form provides a dissolution profile wherein
about 20% to about 65%, about 35% to about 55% or about 40% to
about 50% of the ER dose of acetaminophen remains in the ER layer
between about 1 and 2 hours after administration. In one
embodiment, not more than 50% of the ER dose of acetaminophen is
released within about the first hour. In a further embodiment, not
more than 45% or not more than 40% of the ER dose of acetaminophen
is released within about the first hour. In another embodiment, not
more than 85% of the ER dose of acetaminophen is released within
about 4 hours. In yet another embodiment, not less than 50% is
released after about 6 hours. In yet another embodiment, not less
than 60% is released after about 6 hours. In one embodiment, the ER
dose of acetaminophen is released over a time period of about 6 to
12, about 8 to 10, or about 9 to 10 hours in vitro. In another
embodiment, the ER dose of acetaminophen is released over a time
period of about 7 hours, 8 hours, 9 hours, 10 hours, 11 hours or 12
hours in vitro. In another embodiment, at least 90% or 95% of the
ER dose of acetaminophen is released over a time period of about 7
hours, 8 hours, 9 hours, 10 hours, 11 hours or 12 hours in
vitro.
[0433] In one embodiment, the pharmaceutical compositions disclosed
herein rapidly achieve therapeutic plasma drug levels of oxycodone
and acetaminophen similar to an immediate release product, which
provides an early onset of action within about the first 5 minutes,
10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35
minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes or 60
minutes after administration of the composition, but unlike an
immediate release product, the pharmaceutical composition is able
to maintain those therapeutic plasma drug levels of oxycodone and
acetaminophen over an extended period of time (e.g., up to 12
hours). Currently, there is no pharmaceutical composition available
comprising oxycodone and acetaminophen which is able to provide a
patient with quick onset of analgesia and maintenance of analgesia
for an extended period of time.
[0434] In yet another embodiment, upon average, within one hour of
administration to a subject, the pharmaceutical composition
achieves a Cmax for acetaminophen. The Cmax achieved by the
pharmaceutical composition disclosed herein is comparable to the
Cmax obtained from a commercially-available immediate release
product containing acetaminophen formulated at half the strength of
the commercially-available immediate release product. The
acetaminophen continues to be released from the pharmaceutical
composition at a rate less than the clearance rate for the
acetaminophen, so that the acetaminophen levels fall smoothly until
all of the acetaminophen is absorbed. Stated another way, the
acetaminophen released by the pharmaceutical composition is
eliminated by the body faster than it is being absorbed. The
absorption of the acetaminophen released from the pharmaceutical
composition is complete in about 8 to about 10 hours so that for
one half life of acetaminophen the blood supply reaching the
subject's liver via the portal vein contains no additional amounts
of acetaminophen beyond the amounts present in the subject's
general circulation.
[0435] These additional amounts of acetaminophen delivered to the
liver from the subject's portal vein are frequently caused by the
absorption of acetaminophen in the subject's gastrointestinal
tract. Indeed, blood from the subject's intestines passes through
the liver and then on to the general circulation. When
acetaminophen is undergoing absorption, blood containing
acetaminophen from the absorption process passes through the
subject's liver prior to entering the general circulation where the
acetaminophen is diluted by the distribution and clearance
processes. The metabolism of these higher acetaminophen
concentrations in blood coming into the subject's liver is termed
the "first pass effect." Hence, the absorption process for
acetaminophen taxes a subject's metabolic systems in the liver due
to these higher "first pass" concentrations. Once the absorption
process is complete, the concentration of acetaminophen in the
blood reaching the subject's liver through the portal vein will be
the same concentration of acetaminophen as found in blood
throughout the rest of the subject's body. Thus, the pharmaceutical
compositions disclosed herein provide a Cmax comparable to a
commercially-available immediate-release acetaminophen product
(dosed at half strength) while providing a less taxing burden on
the subject's metabolic systems in the liver because the
acetaminophen released by the pharmaceutical composition is
eliminated by the subject's body faster than it is being absorbed.
This results in decreased levels of acetaminophen in a subject's
liver as compared to an immediate release dosage form of
acetaminophen dosed every 6 hours.
[0436] (i) the Pharmacokinetic Profiles of the Pharmaceutical
Compositions of the Invention are not Affected by the Fed or Fasted
State of the Subject
[0437] Food can play a significant role in both the rate and extent
of absorption of a drug. As is known, the primary function of the
small intestine is to absorb food. During and after a meal, the
intestine normally shows very irregular or unsynchronized
contractions that move the food content back and forth and mix it
with the digestive enzymes that are secreted into the intestine.
However, these contractions are not entirely unsynchronized; they
move the contents of the intestine slowly towards the large
intestine. It normally takes about 90-120 minutes for the first
part of a meal to reach the large intestine, and the last portion
of the meal may not reach the large intestine for five (5) hours.
Between meals, the intestine shows cycles of activity that repeat
about every 90-120 minutes. The cycle consists of a short period of
very few contractions (Phase I), followed by a long period of
unsynchronized contractions that appear similar to the fed pattern
(pre-burst, Phase II), and then a burst of strong, regular
contractions that move down the intestine in a peristaltic fashion
(Phase III). Phase III represents a continuation of the
"housekeeper waves" that start in the stomach; its function is to
sweep undigested food particles and bacteria out of the small
intestine and ultimately into the large intestine.
[0438] Because non-opioid GR dosage forms of the prior art, as well
as prior art extended release opioid formulations, demonstrate food
effects, Applicants expected to likewise see a food effect with the
pharmaceutical compositions of the present invention. Here,
however, Applicants have surprisingly discovered that the
pharmacokinetic profiles of a pharmaceutical composition that
comprises oxycodone and acetaminophen are not substantially
affected by the fed or fasted state of a human subject ingesting
the composition.
[0439] In general, a fed state is defined as having consumed food
within about 30 min prior to administration of the composition. The
food may be a high fat meal, a low fat meal, a high calorie meal,
or a low calorie meal. A fasted state may be defined as not having
ingested food for at least 10 hours prior to administration of the
composition. In some embodiments, the subject may have fasted for
at least 10 hours prior to the first dose and refrains from
ingesting food for at least one hour prior to administration of
subsequent doses. In other embodiments, the fasted subject may not
have ingested food for at least 1 hour, 2 hours, 3 hours, 4 hours,
5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours prior to
administration of each dose of the composition.
[0440] As the pharmacokinetic profiles of a pharmaceutical
composition that comprises oxycodone and acetaminophen are not
substantially affected by the fed or fasted state of a human
subject, there is no substantial difference in the quantity of drug
absorbed or the rate of drug absorption when the
oxycodone/acetaminophen compositions are administered in the fed
versus the fasted state. Without being bound to theory, Applicants
believe that in a fasted state the opioid acts to reduce gastric
motility in an amount sufficient to retain the dosage form in the
stomach thereby mitigating the "housekeeper waves" described
above.
[0441] As shown in Examples 6 and 9, the pharmacokinetic parameters
of the compositions of the invention are similar when the
composition is administered in the fed and fasted states. Benefits
of a dosage form, which substantially eliminates the effect of
food, include an increase in convenience, thereby increasing
patient compliance, as the patient does not need to ensure that
they are taking a dose either with or without food. This is
significant because poor patient compliance can lead to adverse
therapeutic outcomes.
[0442] The invention also encompasses an oxycodone/APAP
pharmaceutical composition in which administration of the
composition to a human subject in a fasted state is bioequivalent
to administration of the composition to a human subject in a fed
state wherein bioequivalence is established by: (1) a 90%
Confidence Interval (CI) for AUC which is between 80% and 125%, and
(2) a 90% CI for Cmax, which is 80% and 125%. In a further
embodiment, the compositions disclosed herein may by administered
to a subject in need thereof without regard to food.
[0443] In other embodiments, the difference in absorption of either
the opioids and/or the APIs of the invention, when administered in
the fed versus the fasted state, is less than about 35%, less than
about 30%, less than about 25%, less than about 20%, less than
about 15%, less than about 10%, less than about 5%, or less than
about 3%. The pharmacokinetic parameter of the other API(s) that is
independent of food may be, but is not limited to, C.sub.max,
C.sub.1hr, C.sub.2hr, AUC, partial AUC, T.sub.max, and T.sub.lag.
Additionally, the opioid(s) in the composition produce a plasma
profile characterized by at least one pharmacokinetic parameter
that differs by less than about 30% under fed and fasted
conditions. In various embodiments, the pharmacokinetic parameter
may vary by less than about 25%, 20%, 15%, 10%, or 5% under fed and
fasted conditions. In one embodiment, the pharmacokinetic parameter
of the opioid that is independent of food may be, but is not
limited to, Cmax, C1 hr, C2 hr, AUC, partial AUC, Tmax, and
Tlag.
(i) Exemplary Compositions
[0444] In one embodiment, the pharmaceutical composition for
extended release of oxycodone and acetaminophen comprises at least
one extended release portion comprising acetaminophen, oxycodone or
a combination thereof, and the at least one extended release
portion of the composition comprises an extended release component
and oxycodone, acetaminophen, or a combination thereof. In yet
another embodiment, the composition comprises an immediate release
portion comprising oxycodone and acetaminophen and an extended
release portion comprising oxycodone, acetaminophen and an extended
release component. In still yet another embodiment, the
compositions comprises two extended release portions, each
comprising an extended release component and one of oxycodone or
acetaminophen, and an immediate release portion comprising
oxycodone and acetaminophen. In another embodiment, the composition
comprises two extended release portions, each comprising an
extended release component and one of oxycodone or acetaminophen,
and two immediate release portions, each comprising one of
oxycodone or acetaminophen. In one embodiment, the extended release
component comprise at least one extended release polymer. In one
exemplary embodiment, the at least one extended release polymer
comprises a polyethylene oxide. The molecular weight of the
polyethylene oxide may be from about 500,000 Daltons to about
10,000,000 Daltons.
[0445] In another embodiment, the pharmaceutical composition may
comprise from about 5 mg to about 30 mg of oxycodone and from about
250 mg to about 1300 mg of acetaminophen. In one embodiment, the
composition may comprise about 15 mg of oxycodone and about 650 mg
of acetaminophen. In another exemplary embodiment, the composition
may comprise about 15 mg of oxycodone and about 500 mg of
acetaminophen. In still another embodiment, the composition may
comprise about 15 mg of oxycodone and about 325 mg of
acetaminophen. In yet another exemplary embodiment, the composition
may comprise about 7.5 mg of oxycodone and about 325 mg of
acetaminophen. In yet another exemplary embodiment, the composition
may comprise about 5 mg of oxycodone and about 325 mg of
acetaminophen. In still another exemplary embodiment, the
pharmaceutical composition may comprise about 10 mg of oxycodone
and about 325 mg of acetaminophen. In a further exemplary
embodiment, the pharmaceutical composition may comprise about 20 mg
of oxycodone and about 650 mg of acetaminophen. In another
exemplary embodiment, the composition may comprise about 30 mg of
oxycodone and about 650 mg of acetaminophen.
[0446] In another embodiment, the composition may comprise from
about 5 mg to about 30 mg of opioid and from about 250 mg to about
1300 mg of at least one other API. In one embodiment, the
composition may comprise about 15 mg of opioid and about 650 mg of
at least one other API. In another embodiment, the composition may
comprise about 15 mg of opioid and about 500 mg of at least one
other API. In a further embodiment, the composition may comprise
about 30 mg of opioid and about 500 mg of at least one other API.
In still another embodiment, the composition may comprise about 15
mg of opioid and about 325 mg of at least one other API. In yet
another exemplary embodiment, the composition may comprise about
7.5 mg of opioid and about 325 mg of at least one other API. In yet
another exemplary embodiment, the composition may comprise about 5
mg of opioid and about 325 mg of at least one other API. In still
another exemplary embodiment, the pharmaceutical composition may
comprise about 10 mg of opioid and about 325 mg of at least one
other API. In a further exemplary embodiment, the pharmaceutical
composition may comprise about 20 mg of opioid and about 650 mg of
at least one other API. In another exemplary embodiment, the
composition may comprise about 30 mg of opioid and about 650 mg of
at least one other API. In yet another exemplary embodiment, the
composition may comprise about 22.5 mg of opioid and about 925 mg
of at least one other API.
[0447] In a further embodiment, a single dosage form of the
pharmaceutical composition disclosed herein (e.g., one tablet) will
provide a subject with approximately the same therapeutic benefit
and pharmacokinetic profile as either two dosage forms (e.g., two
tablets) of the composition formulated at half the strength, or
three dosage forms (e.g., three tablets) of the composition
formulated at a third of the strength. In yet another exemplary
embodiment, the pharmaceutical composition comprising 15 mg of
oxycodone and 650 mg of acetaminophen in a single dosage form
(e.g., one tablet) will provide a subject with approximately the
same therapeutic benefit and pharmacokinetic profile as two dosage
forms of the pharmaceutical composition formulated at half the
strength (e.g., each tablet comprising 7.5 mg of oxycodone and 325
mg of acetaminophen). In still another exemplary embodiment, the
pharmaceutical composition comprising 15 mg of oxycodone and 650 mg
of acetaminophen in a single dosage form (e.g., one tablet) will
provide a subject with approximately the same therapeutic benefit
and pharmacokinetic profile as three dosage forms of the
pharmaceutical composition formulated at a third of the strength
(e.g., each tablet comprising 5 mg of oxycodone and about 216.7 mg
of acetaminophen). In yet another embodiment, the pharmaceutical
composition comprising 15 mg of oxycodone and 325 mg of
acetaminophen in a single dosage form (e.g., one tablet) taken
together with another tablet comprising 7.5 mg of oxycodone and 325
mg of acetaminophen in a single dosage form will provide a subject
with approximately the same therapeutic benefit and pharmacokinetic
profile as a single tablet comprising 22.5 mg of oxycodone and 650
mg of acetaminophen. In still another exemplary embodiment, the
pharmaceutical composition comprising 15 mg of oxycodone and 325 mg
of acetaminophen in a single dosage form (e.g., one tablet) taken
together with another tablet comprising 15 mg of oxycodone and 325
mg of acetaminophen in a single dosage form will provide a subject
with approximately the same therapeutic benefit and pharmacokinetic
profile as a single tablet configuration totaling 30 mg of
oxycodone and 650 mg of acetaminophen. In yet a further exemplary
embodiment, a pharmaceutical composition comprising 21 mg of
oxycodone and 650 mg of acetaminophen in a single dosage form
(e.g., one tablet) will provide a subject with approximately the
same therapeutic benefit and pharmacokinetic profile as two dosage
forms of the pharmaceutical composition formulated at half the
strength (e.g., each tablet comprising 10.5 mg of oxycodone and 325
mg of acetaminophen). In yet another exemplary embodiment, a
pharmaceutical composition comprising 22.5 mg of oxycodone and 925
mg of acetaminophen in a single dosage form (e.g., one tablet) will
provide a subject with approximately the same therapeutic benefit
and pharmacokinetic profile as three dosage forms of the
pharmaceutical composition formulated at a third of the strength
(e.g., each tablet comprising 7.5 mg of oxycodone and 325 mg of
acetaminophen).
[0448] In yet another embodiment, the at least one extended release
portion of the composition may comprise from about 40% to about 60%
(w/w) of the total amount of acetaminophen in the composition and
from about 70% to about 80% (w/w) of the total amount of oxycodone
the composition, whereas the at least one immediate release portion
may comprise from about 40% to about 60% (w/w) of the total amount
of acetaminophen in the composition and from about 20% to about 30%
(w/w) of the total amount of oxycodone in the composition. In still
another embodiment, the at least one extended release portion may
comprise about 50% (w/w) of the total amount of acetaminophen in
the composition and about 75% (w/w) of the total amount of
oxycodone.
[0449] In yet another embodiment, an immediate release portion of
the composition may comprise, by weight of such immediate release
portion, from about 70% to about 80% acetaminophen and from about
0.5% to about 1% of oxycodone, and an extended release portion of
the composition may comprise, by weight of such extended release
portion, from about 30% to about 50% of the extended release
polymer, from about 20% to about 40% of acetaminophen, and from
about 0.5% to about 2% of oxycodone. In another embodiment, the at
least one immediate release portion may comprise about 50% (w/w) of
total amount of acetaminophen in the composition and about 25%
(w/w) of the total amount of oxycodone in the composition.
[0450] In another embodiment, an extended release portion of the
composition may comprise, by weight of such extended release
portion, from about 30% to about 50% of the extended release
polymer, from about 20% to about 40% of acetaminophen, and from
about 0.5% to about 2% of oxycodone; and an immediate release
portion may comprise, by weight of such immediate release portion,
from about 70% to about 80% acetaminophen and from about 0.5% to
about 1% of oxycodone.
[0451] In yet another embodiment, the pharmaceutical composition
may comprise from about 7.5 mg to about 30 mg of oxycodone and from
about 325 mg to about 650 mg of acetaminophen, wherein the at least
one immediate release portion may comprise about 25% (w/w) of the
total amount of oxycodone in the composition and about 50% (w/w) of
the total amount of acetaminophen in the composition, and the at
least one extended release portion may comprise about 75% (w/w) of
the total amount of oxycodone in the composition, about 50% (w/w)
of the total amount of acetaminophen in the composition, and about
35% to about 45%, by weight of the at least one extended release
portion, of an extended release polymer comprising a polyethylene
oxide.
[0452] In yet another embodiment, the pharmaceutical composition
may comprise about 5 mg of oxycodone and about 325 mg of
acetaminophen, wherein the at least one immediate release portion
may comprise about 25% (w/w) of the total amount of oxycodone in
the composition and about 50% (w/w) of the total amount of
acetaminophen in the composition, and the at least one extended
release portion may comprise about 75% (w/w) of the total amount of
oxycodone in the composition, about 50% (w/w) of the total amount
of acetaminophen in the composition.
[0453] In a further embodiment, the pharmaceutical composition may
comprise about 5 mg of oxycodone and about 325 mg of acetaminophen,
wherein the at least one immediate release portion may comprise
about 20% (w/w) to about 30% (w/w) of the total amount of oxycodone
in the composition, and about 40% (w/w) to about 60% (w/w) of the
total amount of acetaminophen in the composition; and the at least
one extended release portion may comprise about 70% (w/w) to about
80% (w/w) of the total amount of oxycodone in the composition and
about 40% (w/w) to about 60% (w/w) of the total amount of
acetaminophen in the composition. The at least one extended release
portion may also comprise about 35% to about 45%, by weight of an
extended release polymer, such as a polyethylene oxide.
[0454] In an additional embodiment, the pharmaceutical composition
may comprise about 5 mg of oxycodone and about 325 mg of
acetaminophen, wherein the at least one immediate release portion
may comprise about 1.25 mg of oxycodone and about 162.5 mg of
acetaminophen, and the at least one extended release portion may
comprise about 3.75 mg of oxycodone and about 162.5 mg of
acetaminophen.
[0455] In still another embodiment, the pharmaceutical composition
may comprise about 5 mg of oxycodone and about 325 mg of
acetaminophen, wherein the at least one immediate release portion
may comprise about 0.75 mg to about 2 mg of oxycodone and about 125
mg to about 325 mg of acetaminophen; and the at least one extended
release portion may comprise about 3 mg to about 4.5 mg of
oxycodone and about 125 mg to about 325 mg of acetaminophen.
[0456] In yet another embodiment, the pharmaceutical composition
may comprise about 7.5 mg of oxycodone and about 325 mg of
acetaminophen, wherein the at least one immediate release portion
may comprise about 25% (w/w) of the total amount of oxycodone in
the composition and about 50% (w/w) of the total amount of
acetaminophen in the composition, and the at least one extended
release portion may comprise about 75% (w/w) of the total amount of
oxycodone in the composition, about 50% (w/w) of the total amount
of acetaminophen in the composition.
[0457] In a further embodiment, the pharmaceutical composition may
comprise about 7.5 mg of oxycodone and about 325 mg of
acetaminophen, wherein the at least one immediate release portion
may comprise about 20% (w/w) to about 30% (w/w) of the total amount
of oxycodone in the composition, and about 40% (w/w) to about 60%
(w/w) of the total amount of acetaminophen in the composition; and
the at least one extended release portion may comprise about 70%
(w/w) to about 80% (w/w) of the total amount of oxycodone in the
composition and about 40% (w/w) to about 60% (w/w) of the total
amount of acetaminophen in the composition. The at least one
extended release portion may also comprise about 35% to about 45%,
by weight of an extended release polymer, such as a polyethylene
oxide.
[0458] In an additional embodiment, the pharmaceutical composition
may comprise about 7.5 mg of oxycodone and about 325 mg of
acetaminophen, wherein the at least one immediate release portion
may comprise about 1.875 mg of oxycodone and about 162.5 mg of
acetaminophen, and the at least one extended release portion may
comprise about 5.625 mg of oxycodone and about 162.5 mg of
acetaminophen.
[0459] In still another embodiment, the pharmaceutical composition
may comprise about 7.5 mg of oxycodone and about 325 mg of
acetaminophen, wherein the at least one immediate release portion
may comprise about 1 mg to about 3 mg of oxycodone and about 125 mg
to about 325 mg of acetaminophen; and the at least one extended
release portion may comprise about 4.75 mg to about 6.5 mg of
oxycodone and about 125 mg to about 325 mg of acetaminophen.
[0460] In yet another embodiment, the pharmaceutical composition
may comprise about 10 mg of oxycodone and about 325 mg of
acetaminophen, wherein the at least one immediate release portion
may comprise about 25% (w/w) of the total amount of oxycodone in
the composition and about 50% (w/w) of the total amount of
acetaminophen in the composition, and the at least one extended
release portion may comprise about 75% (w/w) of the total amount of
oxycodone in the composition, about 50% (w/w) of the total amount
of acetaminophen in the composition.
[0461] In a further embodiment, the pharmaceutical composition may
comprise about 10 mg of oxycodone and about 325 mg of
acetaminophen, wherein the at least one immediate release portion
may comprise about 20% (w/w) to about 30% (w/w) of the total amount
of oxycodone in the composition, and about 40% (w/w) to about 60%
(w/w) of the total amount of acetaminophen in the composition; and
the at least one extended release portion may comprise about 70%
(w/w) to about 80% (w/w) of the total amount of oxycodone in the
composition and about 40% (w/w) to about 60% (w/w) of the total
amount of acetaminophen in the composition. The at least one
extended release portion may also comprise about 35% to about 45%,
by weight of an extended release polymer, such as a polyethylene
oxide.
[0462] In an additional embodiment, the pharmaceutical composition
may comprise about 10 mg of oxycodone and about 325 mg of
acetaminophen, wherein the at least one immediate release portion
may comprise about 2.5 mg of oxycodone and about 162.5 mg of
acetaminophen, and the at least one extended release portion may
comprise about 7.5 mg of oxycodone and about 162.5 mg of
acetaminophen.
[0463] In still another embodiment, the pharmaceutical composition
may comprise about 10 mg of oxycodone and about 325 mg of
acetaminophen, wherein the at least one immediate release portion
may comprise about 1.5 mg to about 3.5 mg of oxycodone and about
125 mg to about 325 mg of acetaminophen; and the at least one
extended release portion may comprise about 6.25 mg to about 8.75
mg of oxycodone and about 125 mg to about 325 mg of
acetaminophen.
[0464] In yet another embodiment, the pharmaceutical composition
may comprise about 15 mg of oxycodone and about 325 mg of
acetaminophen, wherein the at least one immediate release portion
may comprise about 25% (w/w) of the total amount of oxycodone in
the composition and about 50% (w/w) of the total amount of
acetaminophen in the composition, and the at least one extended
release portion may comprise about 75% (w/w) of the total amount of
oxycodone in the composition, about 50% (w/w) of the total amount
of acetaminophen in the composition.
[0465] In a further embodiment, the pharmaceutical composition may
comprise about 15 mg of oxycodone and about 325 mg of
acetaminophen, wherein the at least one immediate release portion
may comprise about 20% (w/w) to about 30% (w/w) of the total amount
of oxycodone in the composition, and about 40% (w/w) to about 60%
(w/w) of the total amount of acetaminophen in the composition; and
the at least one extended release portion may comprise about 70%
(w/w) to about 80% (w/w) of the total amount of oxycodone in the
composition and about 40% (w/w) to about 60% (w/w) of the total
amount of acetaminophen in the composition. The at least one
extended release portion may also comprise about 35% to about 45%,
by weight of an extended release polymer, such as a polyethylene
oxide.
[0466] In an additional embodiment, the pharmaceutical composition
may comprise about 15 mg of oxycodone and about 325 mg of
acetaminophen, wherein the at least one immediate release portion
may comprise about 3.75 mg of oxycodone and about 162.5 mg of
acetaminophen, and the at least one extended release portion may
comprise about 11.25 mg of oxycodone and about 162.5 mg of
acetaminophen.
[0467] In still another embodiment, the pharmaceutical composition
may comprise about 15 mg of oxycodone and about 325 mg of
acetaminophen, wherein the at least one immediate release portion
may comprise about 2.5 mg to about 5 mg of oxycodone and about 125
mg to about 325 mg of acetaminophen; and the at least one extended
release portion may comprise about 10 mg to about 12.5 mg of
oxycodone and about 125 mg to about 325 mg of acetaminophen.
[0468] Other exemplary formulations are set forth in Charts 1-2
below:
TABLE-US-00002 CHART 1 Representative Oxycodone/Acetaminophen
Formulations. Formulation No. 1 2 3 4 5 6 7 8 9 10 Immediate
Release Layer APAP 185.3 175.0 180.0 160.4 200.0 193.4 118.8 162.5
139.0 150.0 Oxycodone hydrochloride 1.100 1.75 2.00 2.50 1.25 1.00
2.75 1.875 1.75 1.875 Microcrystalline cellulose 23.0 17.0 19.0
27.0 16.0 18.0 18.0 14.0 21.0 24.0 Pregelatinized starch 0.05 0.15
0.25 0.10 0.05 0.30 0.20 0.25 0.15 0.20 Citric Acid Anhydrous 0.08
0.08 0.08 0.11 0.11 0.14 0.07 0.13 0.15 0.17 EDTA disodium salt,
0.087 0.106 0.075 0.03 0.050 0.055 0.033 0.025 0.045 0.018
dihydrate Hydroxypropyl cellulose 14.1 17.8 -- -- 17.3 -- 16.7 16.1
21.5 -- Hypromellose 2.5 -- 3.2 -- -- -- -- -- 8.9 19.5
Hydroxypropyl methyl -- -- 21.7 18.3 -- 19.3 -- -- -- 3.0 cellulose
Croscarmellose sodium 10.0 11.0 11.5 11.5 13.0 14.5 14.5 12.5 14.0
12.5 Silicon dioxide 0.97 0.75 1.14 1.02 1.10 1.03 0.88 1.05 0.93
2.30 Magnesium stearate 1.5 1.0 1.0 0.5 0.5 2.0 2.0 0.5 1.5 2.5
Extended APAP 185.3 150.0 145.0 155.2 125.0 100.5 146.9 162.5 207.4
150.0 Oxycodone hydrochloride 6.900 5.75 5.50 5.00 6.25 6.50 7.25
5.625 4.75 6.625 Microcrystalline cellulose 175.4 180.0 302.2 275.0
214.8 250.0 245.7 203.6 288.3 200.5 Pregelatinized starch 0.60 0.60
0.70 0.70 0.70 0.75 0.75 0.75 0.85 0.85 Citric Acid Anhydrous 0.24
0.16 0.24 0.22 0.33 0.28 0.07 0.38 0.45 0.34 EDTA disodium salt,
0.160 0.085 0.095 0.055 0.130 0.065 0.065 0.075 0.130 0.125
dihydrate Hydroxypropyl cellulose 30.0 275.8 95.5 210.6 13.2 40.7
32.9 9.6 -- -- Polyox N12K 292.8 -- -- -- 287.7 -- -- -- 155.5 --
Polyox 1105 -- -- 244.2 -- -- -- 275.5 321.8 -- 189.2 Hydroxypropyl
methyl -- 103.2 -- 134.2 -- 182.2 -- -- 155.5 210.2 cellulose
Silicon Dioxide 1.8 1.3 1.5 2.3 2.4 3.0 3.5 3.6 2.0 2.5 Magnesium
Stearate 7.5 8.0 7.4 8.1 7.5 10.2 9.9 7.2 10.3 10.3 Formulation No.
11 12 13 14 15 16 17 18 19 20 Immediate Release Layer APAP 300.0
150.0 200.0 150.0 100.0 160.0 190.0 75.0 90.0 125.0 Oxycodone
hydrochloride 2.00 1.00 1.50 3.50 2.75 1.25 1.25 2.50 1.75 3.00
Microcrystalline cellulose 21.5 18.5 25.3 35.0 15.7 27.1 9.9 13.9
24.2 16.9 Pregelatinized starch 0.03 0.30 0.25 0.27 0.08 0.35 0.75
0.09 0.15 0.26 Citric Acid Anhydrous 0.12 0.08 0.09 0.16 0.07 0.24
0.14 0.26 0.15 0.20 EDTA disodium salt, 0.04 0.175 0.1 0.06 0.1
0.09 0.06 0.08 0.063 0.09 dihydrate Hydroxypropyl cellulose -- 21.5
1.8 9.8 14.8 -- 20.8 19.2 25.4 -- Hypromellose 2.5 -- -- -- -- --
-- -- 10.3 22.5 Hydroxypropyl methyl 16.3 11.4 17.5 8.7 -- 29.3 --
-- -- 4.4 cellulose Croscarmellose sodium 6.8 11.0 12.8 7.9 19.0
9.6 13.3 15.6 15.1 14.7 Silicon dioxide 0.86 0.80 2.25 1.24 .95
1.34 0.80 1.66 0.79 2.37 Magnesium stearate 1.75 1.0 0.75 0.6 0.5
2.5 1.9 0.8 1.2 2.8 Extended Release APAP 150.0 150.0 125.0 75.0
100.0 165.0 135.0 225.0 210.0 150.0 Oxycodone hydrochloride 8.00
6.50 6.00 6.50 3.25 6.25 6.25 5.00 6.25 5.50 Microcrystalline
cellulose 182.2 197.6 300.4 269.6 210.0 275.5 283.2 310.2 240.8
210.0 Pregelatinized starch 0.75 0.73 0.46 0.89 0.55 0.78 0.55 0.65
0.67 0.64 Citric Acid Anhydrous 0.25 0.36 0.38 0.34 0.37 0.23 0.14
0.40 0.70 0.70 EDTA disodium salt, 0.23 0.09 0.14 0.06 0.183 0.035
0.049 0.03 0.105 0.075 dihydrate Hydroxypropyl cellulose 34.7 321.9
88.4 212.9 11.9 37.7 34.2 17.4 -- -- Polyox N12K -- -- 252.4 --
290.3 -- 248.2 279.2 175.2 -- Polyox 1105 275.8 -- -- -- -- -- --
-- -- 224.5 Hydroxypropyl methyl -- 101.1 -- 110.5 -- 192.1 -- --
140.9 185.6 cellulose Silicon Dioxide 1.3 1.3 1.2 2.4 2.1 3.2 4.0
4.0 2.0 3.8 Magnesium Stearate 5.7 9.4 6.6 5.5 7.7 9.4 6.4 5.2 9.9
7.2 Formulation No. 21 22 23 24 25 26 27 28 29 30 Immediate Release
Layer APAP 185.3 175.0 180.0 160.4 200.0 193.4 118.8 162.5 139.0
150.0 Oxycodone hydrochloride 1.100 1.75 2.00 2.50 1.25 1.00 2.75
1.875 1.75 1.875 Microcrystalline cellulose 23.0 17.0 19.0 27.0
16.0 18.0 18.0 14.0 21.0 24.0 Pregelatinized starch 0.05 0.15 0.25
0.10 0.05 0.30 0.20 0.25 0.15 0.20 Citric Acid Anhydrous 0.08 0.08
0.08 0.11 0.11 0.14 0.07 0.13 0.15 0.17 EDTA disodium salt, 0.087
0.106 0.075 0.03 0.050 0.055 0.033 0.025 0.045 0.018 dihydrate
Hydroxypropyl cellulose 14.1 17.8 -- -- 17.3 -- 16.7 16.1 21.5 --
Hypromellose 2.5 -- 3.2 -- -- -- -- -- 8.9 19.5 Hydroxypropyl
methyl -- -- 21.7 18.3 -- 19.3 -- -- -- 3.0 cellulose
Croscarmellose sodium 10.0 11.0 11.5 11.5 13.0 14.5 14.5 12.5 14.0
12.5 Silicon dioxide 0.97 0.75 1.14 1.02 1.10 1.03 0.88 1.05 0.93
2.30 Magnesium stearate 1.5 1.0 1.0 0.5 0.5 2.0 2.0 0.5 1.5 2.5
Extended Release APAP 185.3 150.0 145.0 155.2 125.0 100.5 146.9
162.5 207.4 150.0 Oxycodone hydrochloride 6.900 5.75 5.50 5.00 6.25
6.50 7.25 5.625 4.75 6.625 Microcrystalline cellulose 175.4 180.0
302.2 275.0 214.8 250.0 245.7 203.6 288.3 200.5 Pregelatinized
starch 0.60 0.60 0.70 0.70 0.70 0.75 0.75 0.75 0.85 0.85 Citric
Acid Anhydrous 0.24 0.16 0.24 0.22 0.33 0.28 0.07 0.38 0.45 0.34
EDTA disodium salt, 0.160 0.085 0.095 0.055 0.130 0.065 0.065 0.075
0.130 0.125 dihydrate Hydroxypropyl cellulose 30.0 275.8 95.5 210.6
13.2 40.7 32.9 9.6 -- -- Polyox N60K 292.8 -- -- -- 287.7 -- -- --
155.5 -- Polyox 205 -- -- 244.2 -- -- -- 275.5 321.8 -- 189.2
Hydroxypropyl methyl -- 103.2 -- 134.2 -- 182.2 -- -- 155.5 210.2
cellulose Silicon Dioxide 1.8 1.3 1.5 2.3 2.4 3.0 3.5 3.6 2.0 2.5
Magnesium Stearate 7.5 8.0 7.4 8.1 7.5 10.2 9.9 7.2 10.3 10.3
Formulation No. 31 32 33 34 35 36 37 38 39 40 Immediate Release
Layer APAP 300.0 150.0 200.0 150.0 100.0 160.0 190.0 75.0 90.0
125.0 Oxycodone hydrochloride 2.00 1.00 1.50 3.50 2.75 1.25 1.25
2.50 1.75 3.00 Microcrystalline cellulose 21.5 18.5 25.3 35.0 15.7
27.1 9.9 13.9 24.2 16.9 Pregelatinized starch 0.03 0.30 0.25 0.27
0.08 0.35 0.75 0.09 0.15 0.26 Citric Acid Anhydrous 0.12 0.08 0.09
0.16 0.07 0.24 0.14 0.26 0.15 0.20 EDTA disodium salt, 0.04 0.175
0.1 0.06 0.1 0.09 0.06 0.08 0.063 0.09 dihydrate Hydroxypropyl
cellulose -- 21.5 1.8 9.8 14.8 -- 20.8 19.2 25.4 -- Hypromellose
2.5 -- -- -- -- -- -- -- 10.3 22.5 Hydroxypropyl methyl 16.3 11.4
17.5 8.7 -- 29.3 -- -- -- 4.4 cellulose Croscarmellose sodium 6.8
11.0 12.8 7.9 19.0 9.6 13.3 15.6 15.1 14.7 Silicon dioxide 0.86
0.80 2.25 1.24 .95 1.34 0.80 1.66 0.79 2.37 Magnesium stearate 1.75
1.0 0.75 0.6 0.5 2.5 1.9 0.8 1.2 2.8 Extended Release APAP 150.0
150.0 125.0 75.0 100.0 165.0 135.0 225.0 210.0 150.0 Oxycodone
hydrochloride 8.00 6.50 6.00 6.50 3.25 6.25 6.25 5.00 6.25 5.50
Microcrystalline cellulose 182.2 197.6 300.4 269.6 210.0 275.5
283.2 310.2 240.8 210.0 Pregelatinized starch 0.75 0.73 0.46 0.89
0.55 0.78 0.55 0.65 0.67 0.64 Citric Acid Anhydrous 0.25 0.36 0.38
0.34 0.37 0.23 0.14 0.40 0.70 0.70 EDTA disodium salt, 0.23 0.09
0.14 0.06 0.183 0.035 0.049 0.03 0.105 0.075 dihydrate
Hydroxypropyl cellulose 34.7 321.9 88.4 212.9 11.9 37.7 34.2 17.4
-- -- Polyox N60K -- 45.5 249.9 24.3 282.0 49.8 200.1 240.1 186.8
-- Polyox 205 268.4 -- 53.6 70.2 -- -- 36.3 10.4 -- 259.3
Hydroxypropyl methyl -- 90.5 -- 65.4 -- 192.1 -- -- 127.3 142.0
cellulose Silicon Dioxide 1.3 1.3 1.2 2.4 2.1 3.2 4.0 4.0 2.0 3.8
Magnesium Stearate 5.7 9.4 6.6 5.5 7.7 9.4 6.4 5.2 9.9 7.2
Formulation No. 41 42 43 44 45 46 47 48 49 50 Immediate Release
Layer APAP 185.3 175.0 180.0 160.4 200.0 193.4 118.8 162.5 139.0
150.0 Oxycodone hydrochloride 1.100 1.75 2.00 2.50 1.25 1.00 2.75
1.875 1.75 1.875 Microcrystalline cellulose 23.0 17.0 19.0 27.0
16.0 18.0 18.0 14.0 21.0 24.0 Pregelatinized starch 0.05 0.15 0.25
0.10 0.05 0.30 0.20 0.25 0.15 0.20 Citric Acid Anhydrous 0.08 0.08
0.08 0.11 0.11 0.14 0.07 0.13 0.15 0.17 EDTA disodium salt, 0.087
0.106 0.075 0.03 0.050 0.055 0.033 0.025 0.045 0.018 dihydrate
Hydroxypropyl cellulose 14.1 17.8 -- -- 17.3 -- 16.7 16.1 21.5 --
Hypromellose 2.5 -- 3.2 -- -- -- -- -- 8.9 19.5 Hydroxypropyl
methyl -- -- 21.7 18.3 -- 19.3 -- -- -- 3.0 cellulose
Croscarmellose sodium 10.0 11.0 11.5 11.5 13.0 14.5 14.5 12.5 14.0
12.5 Silicon dioxide 0.97 0.75 1.14 1.02 1.10 1.03 0.88 1.05 0.93
2.30 Magnesium stearate 1.5 1.0 1.0 0.5 0.5 2.0 2.0 0.5 1.5 2.5
Extended Release APAP 185.3 150.0 145.0 155.2 125.0 100.5 146.9
162.5 207.4 150.0 Oxycodone hydrochloride 6.900 5.75 5.50 5.00 6.25
6.50 7.25 5.625 4.75 6.625 Microcrystalline cellulose 175.4 180.0
302.2 275.0 214.8 250.0 245.7 203.6 288.3 200.5 Pregelatinized
starch 0.60 0.60 0.70 0.70 0.70 0.75 0.75 0.75 0.85 0.85 Citric
Acid Anhydrous 0.24 0.16 0.24 0.22 0.33 0.28 0.07 0.38 0.45 0.34
EDTA disodium salt, 0.160 0.085 0.095 0.055 0.130 0.065 0.065 0.075
0.130 0.125 dihydrate Hydroxypropyl cellulose 30.0 275.8 95.5 210.6
13.2 40.7 32.9 9.6 -- -- Polyox N-750 292.8 -- -- -- 287.7 -- -- --
155.5 -- Polyox 301 -- -- 244.2 -- 13 -- 275.5 321.8 -- 189.2
Hydroxypropyl methyl -- 103.2 -- 134.2 -- 182.2 -- -- 155.5 210.2
cellulose Silicon Dioxide 1.8 1.3 1.5 2.3 2.4 3.0 3.5 3.6 2.0 2.5
Magnesium Stearate 7.5 8.0 7.4 8.1 7.5 10.2 9.9 7.2 10.3 10.3
Formulation No. 51 52 53 54 55 56 57 58 59 60 Immediate Release
Layer APAP 300.0 150.0 200.0 150.0 100.0 160.0 190.0 75.0 90.0
125.0 Oxycodone hydrochloride 2.00 1.00 1.50 3.50 2.75 1.25 1.25
2.50 1.75 3.00 Microcrystalline cellulose 21.5 18.5 25.3 35.0 15.7
27.1 9.9 13.9 24.2 16.9 Pregelatinized starch 0.03 0.30 0.25 0.27
0.08 0.35 0.75 0.09 0.15 0.26 Citric Acid Anhydrous 0.12 0.08 0.09
0.16 0.07 0.24 0.14 0.26 0.15 0.20 EDTA disodium salt, 0.04 0.175
0.1 0.06 0.1 0.09 0.06 0.08 0.063 0.09 dihydrate Hydroxypropyl
cellulose -- 21.5 1.8 9.8 14.8 -- 20.8 19.2 25.4 -- Hypromellose
2.5 -- -- -- -- -- -- -- 10.3 22.5 Hydroxypropyl methyl 16.3 11.4
17.5 8.7 -- 29.3 -- -- -- 4.4 cellulose Croscarmellose sodium 6.8
11.0 12.8 7.9 19.0 9.6 13.3 15.6 15.1 14.7 Silicon dioxide 0.86
0.80 2.25 1.24 .95 1.34 0.80 1.66 0.79 2.37 Magnesium stearate 1.75
1.0 0.75 0.6 0.5 2.5 1.9 0.8 1.2 2.8 Extended Release APAP 150.0
150.0 125.0 75.0 100.0 165.0 135.0 225.0 210.0 150.0 Oxycodone
hydrochloride 8.00 6.50 6.00 6.50 3.25 6.25 6.25 5.00 6.25 5.50
Microcrystalline cellulose 182.2 197.6 300.4 269.6 210.0 275.5
283.2 310.2 240.8 210.0 Pregelatinized starch 0.75 0.73 0.46 0.89
0.55 0.78 0.55 0.65 0.67 0.64 Citric Acid Anhydrous 0.25 0.36 0.38
0.34 0.37 0.23 0.14 0.40 0.70 0.70 EDTA disodium salt, 0.23 0.09
0.14 0.06 0.183 0.035 0.049 0.03 0.105 0.075 dihydrate
Hydroxypropyl cellulose 34.7 321.9 88.4 212.9 11.9 37.7 34.2 17.4
-- -- Polyox N-750 63.4 30.1 125.9 100.3 149.2 63.2 150.5 140.3
94.3 -- Polyox 301 210.4 -- 175.8 60.7 175.8 -- 160.5 149.7 100.8
194.6 Hydroxypropyl methyl -- 128.3 -- 65.4 -- 227.7 -- -- 127.3
142.0 cellulose Silicon Dioxide 1.3 1.3 1.2 2.4 2.1 3.2 4.0 4.0 2.0
3.8 Magnesium Stearate 5.7 9.4 6.6 5.5 7.7 9.4 6.4 5.2 9.9 7.2 *All
weights in mg.
TABLE-US-00003 CHART 2 Additional Oxycodone/Acetaminophen
Formulations. Formulation No. 61 62 63 64 65 66 67 68 69 70
Immediate Release Layer APAP 250.0 250.0 250.0 250.0 250.0 250.0
325.0 325.0 162.5 162.5 Oxycodone hydrochloride 3.75 3.75 3.75 7.5
7.5 7.5 3.75 3.75 2.5 3.75 Microcrystalline cellulose 23.72 23.72
23.72 32.42 32.42 32.42 28.10 28.10 15.50 18.40 Pregelatinized
starch 0.50 0.50 0.50 1.00 1.00 1.00 0.50 0.50 0.33 0.50 Citric
Acid Anhydrous 0.25 0.25 0.25 0.50 0.50 0.50 0.25 0.25 0.17 0.25
EDTA disodium salt, 0.05 0.05 0.05 0.10 0.10 0.10 0.05 0.05 0.033
0.05 dihydrate Hydroxypropyl cellulose 25.23 25.23 25.23 26.43
26.43 26.43 32.24 32.23 16.32 16.72 Croscarmellose sodium 19.21
19.21 19.21 20.13 20.13 20.13 12.09 25.087 12.70 13.01 Silicon
dioxide 1.63 1.63 1.63 1.70 1.70 1.70 2.09 2.09 1.06 1.08 Magnesium
stearate 0.81 0.81 0.81 0.85 0.85 0.85 1.045 1.045 0.53 0.54
Extended Release Layer APAP 250.0 250.0 250.0 250.0 250.0 250.0
325.0 325.0 162.5 162.5 Oxycodone hydrochloride 11.25 11.25 11.25
22.5 22.5 22.5 11.25 11.25 7.5 11.25 Microcrystalline cellulose
175.24 103.74 103.74 159.62 88.12 88.12 23.85 23.85 201.02 195.80
Pregelatinized starch 1.50 1.50 1.50 3.00 3.00 3.00 1.50 1.50 1.00
1.50 Citric Acid Anhydrous 0.75 0.75 0.75 1.50 1.50 1.50 0.75 0.75
0.50 0.75 EDTA disodium salt, 0.15 0.15 0.15 0.30 0.30 0.30 0.15
0.15 0.10 0.15 dihydrate Hydroxypropyl cellulose 15.13 15.13 15.13
17.11 17.11 17.11 -- 19.16 9.91 10.57 Polyox 1105 250.25 321.75 --
250.25 321.75 -- 321.02 321.02 321.75 321.75 Polyox N60K -- --
321.75 -- -- 321.75 -- -- -- -- Silicon Dioxide 3.58 3.58 3.58 3.58
3.58 3.58 3.57 3.57 3.58 3.58 Magnesium Stearate 7.15 7.15 7.15
7.15 7.15 7.15 7.13 7.13 7.15 7.15 *All weights in mg.
III. METHODS FOR PREPARING SOLID DOSAGE FORMS OF THE PHARMACEUTICAL
COMPOSITION
[0469] Another aspect of the disclosure provides methods for
preparing solid dosage forms of the pharmaceutical composition that
provide extended release of oxycodone and acetaminophen. Solid
dosage compositions in the form of tablets may be produced using
any suitable method known in the art including but not limited to
wet granulation, dry granulation, direct compression, and
combinations thereof.
[0470] Granulation is a manufacturing process which increases the
size and homogeneity of active pharmaceutical ingredients and
excipients that comprise a solid dose composition. The granulation
process, which is often referred to as agglomeration, changes
important physical characteristics of the dry composition, with the
aim of improving manufacturability and, thereby, product quality,
as well as providing desired release kinetics. Wet granulation is
by far the more prevalent agglomeration process utilized within the
pharmaceutical industry. Most wet granulation procedures follow
some basic steps; the active agent(s) and excipients are mixed
together, and a binder solution is prepared and added to the powder
mixture to form a wet mass. The moist particles are then dried and
sized by milling or by screening through a sieve. In some cases,
the wet granulation is "wet milled" or sized through screens before
the drying step. The wet granulation process may be a high shear
granulation process or a fluid bed granulation process. Several
methods of granulation are described in co-pending application U.S.
application Ser. No. 13/166,770, filed Jun. 22, 2011, which is
incorporated herein by reference in its entirety.
[0471] After granulation and drying of the resultant particles,
batches are characterized with respect to properties such as final
Loss on Drying (LOD), bulk density, tap density, and particle size.
Loss on Drying (LOD) typically is determined after each granulation
using the Moisture Analyzer. Several 1 g samples may be taken and
loaded into the moisture analyzer. The samples may be run for 5
minutes at a temperature of 105.degree. C. In another embodiment,
the samples may be run at 105.degree. C. until there is no weight
fluctuation in order to determine the LOD.
[0472] Bulk and tap densities may be determined as follows. A
graduated cylinder is filled with a certain amount of material
(e.g., 30-40 g or 82-88 g), and the volume recorded to determine
the material bulk density. Tap density can be determined with a
help of a Tap Density Tester by exposing the material to 100 taps
per test and recording the new volume.
[0473] Particle size determination generally is performed
immediately after granulation, after sieving through 20 mesh screen
to remove agglomerates. Particle diameter may be determined with a
sieve-type particle diameter distribution gauge using sieves with
openings of 30, 40, 60, 80, 120, and 325 mesh. Fractions may be
weighed on a Mettler balance to estimate size distribution. This
provides determination of the quantitative ratio by particle
diameter of composition comprising extended release particles.
Sieve analysis according to standard United States Pharmacopoeia
methods (e.g., USP-23 NF 18), may be done such as by using a
Meinzer II Sieve Shaker.
[0474] In one embodiment, the method for preparing dosage forms of
the pharmaceutical composition may comprise wet granulating a first
mixture comprising the opioid, such as oxycodone, the API, such as
acetaminophen, and a binder to produce a first granulation mixture.
The wet granulation process may be a fluid bed granulation process.
In additional embodiments, the first mixture may further comprise
at least one additional excipient selected from the group
consisting of fillers, lubricants, antioxidants, chelating agents,
and color agents. The first granulation mixture may be blended with
an extended release polymer and one or more excipients, as listed
above, to form at least one extended release portion of a dosage
form. In certain embodiments, the extended release polymer may be a
polyethylene oxide.
[0475] In another embodiment, the method further comprises wet
granulating a second mixture comprising the opioid, such as
oxycodone, the API, such as acetaminophen, and a binder to form a
second granulation mixture. The wet granulation process may be a
fluid bed granulation process. In some embodiments, the second
mixture may further comprise at least one additional excipient
selected from the group consisting of fillers, lubricants,
disintegrants, antioxidants, chelating agents, and color agents.
The second granulation mixture may be blended with one or more
excipients, as listed above, to form an immediate release portion
of a dosage form.
[0476] In an additional embodiment, the method may further comprise
compressing the at least one extended release portion and the at
least one immediate release portion into a tablet. The tablet may
be a bilayer tablet. The tablet may be coated with a tablet
coating.
[0477] In another embodiment, the method may comprise granulating
via a high shear wet granulation process a mixture comprising the
opioid (e.g., oxycodone) and at least one excipient to form opioid
(e.g., oxycodone) particles. The opioid particles may be dried at a
suitable temperature. The opioid particles may be granulated via a
fluid bed granulation process with the API (e.g., acetaminophen), a
binder, and an optional excipient to form the granulation mixture.
The granulation mixture may be blended with an extended release
polymer and at least one excipient to form an extended release
portion of a solid dosage form.
[0478] In a further embodiment, the method may further comprise
granulating via a fluid bed granulation process opioid particles
with the API, a binder, and an optional excipient to form another
granulation mixture. This granulation mixture may be blended with
one or more excipients to form an immediate release portion of a
solid dosage form.
[0479] In an additional embodiment, the method may further comprise
compressing the at least one extended release portion comprising
opioid particles and the at least one immediate release portion
comprising opioid particles into a tablet. In one embodiment, the
method comprises compressing one extended release portion
comprising opioid particle and one immediate release portion
comprising opioid particles into a bilayer tablet. The tablet may
be coated with a tablet coating.
[0480] In another embodiment, wet granulation of either mixture may
produce particles with a bulk density ranging from about 0.30 to
0.40 grams/milliliter (g/mL). In other aspects, the wet granulation
may produce particles with a tap density ranging from about 0.35
g/mL to about 0.45 g/mL. In other embodiments, the wet granulation
may produce particles, wherein at least about 50% of the particles
have a size greater than 125 microns. In still other embodiments,
the wet granulation may produce particles wherein about 20% to
about 65% of the particles have a size greater than about 125
microns and less than about 250 microns.
[0481] Tablets generally are characterized with respect to
disintegration and dissolution release profiles as well as tablet
hardness, friability, and content uniformity.
[0482] In vitro dissolution profiles for the tablets may be
determined using a USP Type II apparatus, with a paddle speed of
either about 100 rpm or 150 rpm, in 0.1 N HCl, at 37.degree. C.
Samples of 5 mL at each time-point, may be taken without media
replacement at 0.08, 0.25, 0.5, 1, 2, 4, 6, 8 and 12 hours, for
example. In some embodiments, the dissolution profiles may be
determined at varying pH values, such as at a pH of about 3.0, 3.5,
4.0, 4.5, 5.0, 5.5, 6.0 or 6.5. The fluid used may be, for example,
HCl, phosphate buffer, or simulated gastric fluid. The resulting
cumulative dissolution profiles for the tablets are based upon a
theoretical percent active added to the pharmaceutical
compositions.
[0483] A tablet preferably disintegrates before it dissolves. A
disintegration tester measures the time it takes a tablet to break
apart in solution. The tester suspends tablets in a solution bath
for visual monitoring of the disintegration rate. Both the time to
disintegration and the disintegration consistency of all tablets
may be measured. The disintegration profile may be determined in a
USP Disintegration Tester in pH 5.8 phosphate buffer or 0.1 N HCl
of pH 1.2. The fluid used may be, for example, HCl, phosphate
buffer, or simulated gastric fluid. Samples, 1-5 mL at each
time-point, may be taken, for example, without media replacement at
0.5, 1, 2, 3, 4, 5, 6, 7 and 8 hours. The resulting cumulative
disintegration profiles are based upon a theoretical percent active
added to the pharmaceutical compositions.
[0484] After tablets are formed by compression, it is desired that
the tablets have a strength of at least 9-25 Kiloponds (kp), or at
least about 12-20 (kp). A hardness tester generally is used to
determine the load required to diametrically break the tablets
(crushing strength) into two equal halves. The fracture force may
be measured using a Venkel Tablet Hardness Tester, using standard
USP protocols.
[0485] Friability is a well-known measure of a tablet's resistance
to surface abrasion that measures weight loss in percentage after
subjecting the tablets to a standardized agitation procedure.
Friability properties are especially important during any transport
of the dosage form as any fracturing of the final dosage form may
result in a subject receiving less than the prescribed medication.
Friability may be determined using a Roche Friability Drum
according to standard USP guidelines which specifies the number of
samples, the total number of drum revolutions, and the drum rpm to
be used. Friability values of from 0.8 to 1.0% generally are
regarded as constituting the upper limit of acceptability.
[0486] The prepared tablets generally are tested for content
uniformity to determine if they meet the pharmaceutical requirement
of an acceptance value of 15 or less. Each tablet may be placed in
a solution of 60% methanol/40% isopropanol and stirred at room
temperature until the tablet disintegrates. The solution containing
the dissolved tablet may be further diluted in 90% water/10%
isopropanol/0.1% heptafluorobutyric acid and generally is analyzed
by HPLC.
IV. METHOD FOR REDUCING THE RISK OF ACETAMINOPHEN-INDUCED HEPATIC
DAMAGE
[0487] The present disclosure also provides methods for reducing
the risk of acetaminophen-induced hepatic damage in a subject being
treated for pain with a dosage regimen that comprises administering
to the subject at least two consecutive doses of a pharmaceutical
composition comprising oxycodone and acetaminophen. The method
comprises administering a first dose of a pharmaceutical
composition comprising at least one extended release portion
comprising the acetaminophen, the oxycodone or a combination
thereof, and an extended release component to the subject, wherein
the composition maintains a therapeutic blood plasma concentration
of oxycodone of at least 5 ng/mL from about 0.75 hours to about 10
hours after administration of the composition, and wherein at least
about 90% of the acetaminophen is released from the composition by
about 8 hours after administration of the composition such that, by
about 10 hours after administration of the composition,
acetaminophen has a blood plasma concentration that is less than
about 30% of acetaminophen's maximum plasma concentration. The
method further comprises administering a second dose of the
pharmaceutical composition to the subject at about 12 hours after
administration of the first dose.
[0488] Avoiding toxic intermediate formation is an important
strategy in addressing product safety. Indeed, acetaminophen is
absorbed from the stomach and small intestine and primarily
metabolized by conjugation in the liver to nontoxic, water-soluble
compounds that are eliminated in the urine. When the maximum daily
dose ("MDD") is exceeded over a prolonged period, metabolism by
conjugation becomes saturated, and excess acetaminophen is
oxidatively metabolized by the CYP enzymes (CYP2E1, 1A2, 2A6, 3A4)
to a reactive metabolite, N-acetyl-p-benzoquinone-imine (NAPQI).
NAPQI has an extremely short half-life, and rapidly conjugates with
available glutathione, which acts as a sulfhydryl donor. The
reduced NAPQI is then renally excreted. The liver plays a central
role in the turnover of glutathione in the body. Given that
toxicity due to NAPQI formation occurs via necrosis of the liver
following the formation of toxic adducts, minimizing glutathione
depletion and enhancing glutathione regeneration in the liver is an
important concern.
[0489] Human erythrocyte data resulting from hepatic turnover
demonstrate a time-delayed response to redox and free radical
insults via glutathione depletion and regeneration. The hepatic
dynamics of glutathione formation and depletion in animal data
using hepatic models can also be reviewed. In Swiss mice, the
dynamics of glutathione depletion was investigated in detail for
acetaminophen doses ranging from (100 mg/kg to 600 mg/kg) in work
done by Brzeznicka and Piotrowski (1989). Under one embodiment of
the present invention, the intended dosage for patients with acute
pain is 1.3 g/day of acetaminophen. Assuming a subject's weight of
70 kg, this is 1.229.times.10-4 moles/kg/day in human subjects. In
Swiss mice, 400 mg/kg and 600 mg/kg are 2.65.times.10-3
moles/kg/day and 3.97.times.10-3 moles/kg/day, respectively,
resulting in a 22-fold and a 32-fold safety exposure ratio, as
compared with human levels. The bioequivalence level is 95%.
Brzeiznicka and Piotrowski report that circulating hepatic GSH
changes in mice began within 15 min after acetaminophen
administration, and depletion followed a pattern that was strictly
dose dependent, reaching a minimum GSH level 2 hrs after injection
for the all dose groups, rebounding to initial levels between hours
8 and 12. Taken together, these results support the hypothesis that
exposing subjects to the lower end of the therapeutic window of
acetaminophen may provide benefit in terms of the patient's ability
to regenerate physiologically protective levels of glutathione.
Thus, the pharmaceutical formulations disclosed herein, which are
designed to allow for a two hour break in acetaminophen exposure in
each twelve hour exposure window allows for restorative hepatic
regeneration of the subject's glutathione levels during that period
when the acetaminophen concentrations are at their lowest or
absent, while still preserving the considerable benefits of the
potentiating effects of combination analgesia.
[0490] As mentioned above, acetaminophen is primarily metabolized
via conjugation reactions, e.g., glucuronidation and sulfation, in
the liver to nontoxic, water-soluble compounds that are rapidly
eliminated from the body. A small proportion of acetaminophen is
metabolized by the cytochrome P450 system to the reactive
metabolite, NAPQI. Generally, this toxic metabolite is rapidly
detoxified by conjugation to glutathione to form a non-toxic
metabolite that is renally excreted. However, if the conjugation
pathways become saturated and more acetaminophen is metabolized via
the cytochrome P450 pathway, the pool of available glutathione may
become depleted. With insufficient glutathione to bind to and
inactivate NAPQI, this toxic metabolite is able to react with the
sulfhydryl groups of cellular proteins initiating a cascade of
cellular damage, which may lead to liver necrosis, and, ultimately,
liver failure.
[0491] The method disclosed herein addresses the problem of
depleted stores of glutathione by providing a period of time during
the later part of the dosing interval during which the release of
acetaminophen is low because most of the acetaminophen has already
been released from the composition. The period of time during which
the release of acetaminophen is low is called the acetaminophen
"time-off" period. As a consequence of this acetaminophen time-off
period, the plasma levels of acetaminophen fall to sufficiently low
levels such that the metabolic burden on the liver is reduced,
thereby allowing the depleted stores of glutathione to be
replenished via the continuous glutathione manufacturing pathway
comprising the glutathione synthase pathway. Because the levels of
glutathione are able to be restored before the next dose, the risk
of acetaminophen-induced hepatic damage is significantly
reduced.
[0492] Additionally, the acetaminophen time-off period provided by
the compositions disclosed herein may provide an added and
beneficial precaution for any subject undergoing acetaminophen
therapy to avoid an inadvertent reduction in glutathione stores and
any potential acetaminophen-induced hepatic damage. In particular,
the acetaminophen time-off period provided by the compositions
disclosed herein may be especially useful during chronic
administration of analgesic compositions comprising acetaminophen.
The subject may be at increased risk for developing
acetaminophen-induced hepatic damage because of frequent and
regular user of alcohol (i.e., ethanol), concurrent administration
of acetaminophen from another source (e.g., an over-the-counter
medication), poor diet, and/or compromised liver function.
[0493] In general, the compositions disclosed herein are formulated
such that the rate of release of acetaminophen is high during the
first several hours of the dosing interval and the rate of release
of acetaminophen is low during the last several hours of the dosing
interval. More specifically, the compositions are formulated to
release from about 40% to about 65% of the acetaminophen in about
30 minutes, from about 55% to about 80% of the acetaminophen in
about 2 hours, from about 65% to about 92% of the acetaminophen in
about 4 hours, and from about 67% to about 95% of the acetaminophen
in about 8 hours, wherein the dosing interval is about 12 hours. In
another, the compositions are formulated to release from about 45%
to about 60% of the acetaminophen in about 30 minutes, from about
57% to about 75% of the acetaminophen in about 2 hours, from about
67% to about 90% of the acetaminophen in about 4 hours, and from
about 70% to about 95% of the acetaminophen in about 8 hours,
wherein the dosing interval is about 12 hours. In yet another
embodiment, during the final 4 hours of a 12 hour dosing interval,
only about 5% of the acetaminophen remains to be released from the
composition.
[0494] The subject may be a mammal, and in certain embodiments, the
subject may be a human. In various embodiments, the at least two
consecutive doses of the analgesic composition may be administered
to the subject at 8 hour intervals, 10 hour intervals, 12 hour
intervals, 18 hour intervals, or 24 hour intervals.
[0495] The method for reducing the risk of acetaminophen-induced
hepatic damage disclosed herein may further comprise administering
additional doses of the pharmaceutical composition at regular
dosing intervals, such as e.g., at 12 hour intervals. During the
latter part of each dosing interval, therefore, the acetaminophen
time-off period allows depleted stores of glutathione to be
replenished, thereby reducing the risk of acetaminophen-induced
hepatic damage in subjects being treated for pain with a
composition comprising acetaminophen.
V. METHOD FOR TREATING PAIN
[0496] Also provided is a method for treating pain in a subject in
need of such treatment with a pharmaceutical composition that
comprises an opioid, such as oxycodone, and an additional API, such
as acetaminophen, wherein the method comprises administering an
effective amount of any of the pharmaceutical compositions
disclosed herein. For example, the method comprises orally
administering to the subject an effective amount of a
pharmaceutical composition comprising at least one extended release
portion comprising oxycodone, acetaminophen and combination
thereof, and an extended release component, wherein the composition
maintains a therapeutic plasma concentration of oxycodone of at
least about 5 ng/mL from about 0.75 hour to about 10 hours after
administration of the composition, and wherein at least about 90%
of the acetaminophen is released from the composition by about 8
hours after administration of the composition such that, by about
10 hours after administration of the composition, acetaminophen has
a blood plasma concentration that is less than about 30% of
acetaminophen's maximum plasma concentration.
[0497] In some embodiments, the subject may be suffering from or
diagnosed with chronic pain. In yet another embodiment, the subject
may be suffering from or diagnosed with acute pain. In still
another embodiment, the subject may be suffering from or diagnosed
with moderate to severe acute pain. In yet other embodiments, the
subject may be suffering from or diagnosed with both chronic and
acute pain. The subject may be a mammal, and in certain
embodiments, the subject may be a human.
[0498] In additional embodiments, the method comprises orally
administering to the subject an effective amount of a gastric
retentive pharmaceutical composition to the subject, wherein the
subject is in a fasted state. Moreover, upon administration of the
pharmaceutical composition, the opioid in the composition produces
a plasma profile characterized by at least one pharmacokinetic
parameter that differs by less than about 30% when the subject is
in a fasted state as compared to a fed state.
[0499] The pharmacokinetic parameter of the active agent(s) of the
pharmaceutical composition that differs by less that about 30%
under fed and fasted conditions may be, but is not limited to,
C.sub.max, C.sub.1hr, C.sub.2hr, AUC, partial AUC, T.sub.max, and
T.sub.lag. In various embodiments, the pharmacokinetic parameter
may vary by less than about 25%, 20%, 15%, 10%, or 5% under fed and
fasted conditions.
[0500] In embodiments in which the pharmaceutical composition
comprises oxycodone and acetaminophen, the C.sub.max or AUC of
oxycodone and the C.sub.max or AUC of acetaminophen may each
individually vary by less than about 30%, 29%, 28%, 27%, 26%, 25%,
24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%. 13%, 12%,
11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% under fed and
fasted conditions.
[0501] In some embodiments, an effective amount of the
pharmaceutical composition may be administered to a subject in a
fed state. In general, a fed state is defined as having consumed
food within about 30 min prior to administration of the
pharmaceutical composition. The food may be a high fat meal, a low
fat meal, a high calorie meal, or a low calorie meal. In other
embodiments, an effective amount of the pharmaceutical composition
may be administered to a subject in a fasted state. In general, a
fasted state is defined as not having ingested food for at least 10
hours prior to administration of the pharmaceutical composition. In
some embodiments, the pharmaceutical composition may be
administered to a subject who has fasted for at least 10 hours
prior to the first dose and who fasts for at least one hour prior
to administration of subsequent doses. In other embodiments, the
pharmaceutical composition may be administered to a subject who has
fasted for at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6
hours, 7 hours, 8 hours, 9 hours, or 10 hours prior to
administration of each dose.
[0502] An effective amount of the pharmaceutical composition may
comprise from about 5 mg to about 300 mg of the opioid and from
about 100 mg to about 1300 mg of the other API. In embodiments in
which the opioid is oxycodone and the API is acetaminophen, the
pharmaceutical composition may comprise from about 7.5 mg to about
30 mg of oxycodone and from about 250 mg to about 1300 mg of
acetaminophen.
[0503] In one embodiment, an effective amount of the pharmaceutical
composition may be 15 mg of oxycodone and 650 mg of acetaminophen.
For example, one solid dosage form comprising 15 mg of oxycodone
and 650 mg of acetaminophen may be administered. Alternatively, two
solid dosage forms with each comprising 7.5 mg of oxycodone and 325
mg of acetaminophen may be administered. In another embodiment, an
effective amount of the pharmaceutical composition may be 7.5 mg of
oxycodone and 325 mg of acetaminophen, wherein one solid dosage
form comprising 7.5 mg of oxycodone and 325 mg of acetaminophen may
be administered. In yet another embodiment, the effective amount of
a pharmaceutical composition may be 20 mg of oxycodone and 650 mg
of acetaminophen. For example, one solid dosage form comprising 20
mg of oxycodone and 650 mg of acetaminophen may be administered.
Alternatively, two solid dosage forms with each comprising 10 mg of
oxycodone and 325 mg of acetaminophen may be administered. In
another embodiment, the effective amount of a pharmaceutical
composition may be 10 mg of oxycodone and 325 mg of acetaminophen,
wherein one solid dosage form comprising 10 mg of oxycodone and 325
mg of acetaminophen may be administered. In still yet another
embodiment, the effective amount of a pharmaceutical composition
may be 30 mg of oxycodone and 650 mg of acetaminophen. For example,
one solid dosage form comprising 30 mg of oxycodone and 650 mg of
acetaminophen may be administered. Alternatively, two solid dosage
forms with each comprising 15 mg of oxycodone and 325 mg of
acetaminophen may be administered. In another embodiment, the
effective amount of a pharmaceutical composition may be 15 mg of
oxycodone and 325 mg of acetaminophen, wherein one solid dosage
form comprising 15 mg of oxycodone and 325 mg of acetaminophen may
be administered.
[0504] The dosing intervals of the effective amount of the
pharmaceutical composition can and will vary. For example, an
effective amount of the pharmaceutical composition may be
administered once a day, twice a day, or three times a day. In
another embodiment, an effective amount of the pharmaceutical
composition may be administered twice a day.
[0505] In general, therapeutic plasma concentrations of the opioid
(e.g., oxycodone) and the additional API (e.g., acetaminophen) are
attained within about 5 minutes, 10 minutes, 15 minutes, 20
minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45
minutes, 50 minutes, 55 minutes, or 60 minutes after administration
of the first dose of the pharmaceutical composition. Accordingly,
depending upon the severity of the pain, onset on analgesia may be
attained within about 5 minutes, 10 minutes, 15 minutes, 20
minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45
minutes, 50 minutes, 55 minutes, or 60 minutes after administration
of the composition. Onset of analgesia may be measured by the
double stopwatch method or other pain assessments as described in
Example 12 below. Generally, analgesia or pain relief will be
maintained throughout the duration of the dosing interval. For
example, in one embodiment, analgesia or pain relief will be
maintained for 12 hours. Upon administration of the next dose of
the pharmaceutical composition, therefore, analgesia or pain relief
may be maintained. Accordingly, analgesia or pain relief will be
maintained as long as therapeutic amounts of the pharmaceutical
composition are administered at regular dosing intervals. Moreover,
pain relief may be managed such that no break-through episodes of
pain occur.
[0506] The extended-release formulations of the present invention
are useful for treating numerous pain states that are currently
being treated with conventional immediate release compositions
comprising acetaminophen and oxycodone. These and additional pain
states include, by way of illustration and not limitation, headache
pain, pain associated with migraine, neuropathic pain selected from
the group consisting of diabetic neuropathy, HIV sensory
neuropathy, post-herpetic neuralgia, post-thoracotomy pain,
trigeminal neuralgia, radiculopathy, neuropathic pain associated
with chemotherapy, reflex sympathetic dystrophy, back pain,
peripheral neuropathy, entrapment neuropathy, phantom limb pain,
and complex regional pain syndrome, dental pain, pain associated
with a surgical procedure and or other medical intervention, bone
cancer pain, joint pain associated with psoriatic arthritis,
osteoarthritic pain, rheumatoid arthritic pain, juvenile chronic
arthritis associated pain, juvenile idiopathic arthritis associated
pain, Spondyloarthropathies (such as ankylosing spondylitis (Mb
Bechterew) and reactive arthritis (Reiters syndrome) associated
pain), pain associated with psoriatic arthritis, gout pain, pain
associated with pseudogout (pyrophosphate arthritis), pain
associated with systemic lupus erythematosus (SLE), pain associated
with systemic sclerosis (scleroderma), pain associated with
Behcet's disease, pain associated with relapsing polychondritis,
pain associated with adult Still's disease, pain associated with
transient regional osteoporosis, pain associated with neuropathic
arthropathy, pain associated with sarcoidosis, arthritic pain,
rheumatic pain, joint pain, osteoarthritic joint pain, rheumatoid
arthritic joint pain, juvenile chronic arthritis associated joint
pain, juvenile idiopathic arthritis associated joint pain,
Spondyloarthropathies (such as ankylosing spondylitis (Mb
Bechterew) and reactive arthritis (Reiter's syndrome) associated
joint pain), gout joint pain, joint pain associated with pseudogout
(pyrophosphate arthritis), joint pain associated with systemic
lupus erythematosus (SLE), joint pain associated with systemic
sclerosis (scleroderma), joint pain associated with Behcet's
disease, joint pain associated with relapsing polychondritis, joint
pain associated with adult Still's disease, joint pain associated
with transient regional osteoporosis, joint pain associated with
neuropathic arthropathy, joint pain associated with sarcoidosis,
arthritic joint pain, rheumatic joint pain, acute pain, acute joint
pain, chronic pain, chronic joint pain, inflammatory pain,
inflammatory joint pain, mechanical pain, mechanical joint pain,
pain associated with the fibromyalgia syndrome (FMS), pain
associated with polymyalgia rheumatica, monarticular joint pain,
polyarticular joint pain, nociceptive pain, psychogenous pain, pain
of unknown etiology, pain mediated by IL-6, IL-6 soluble receptor,
or IL-6 receptor, pain associated with a surgical procedure in a
patient with a clinical diagnosis of OA, pain like static
allodynia, pain like dynamic allodynia, and/or pain associated with
Crohn's disease.
[0507] It is to be understood that any ranges, ratios and ranges of
ratios that can be formed by, or derived from, any of the data
disclosed herein represent further embodiments of the present
disclosure and are included as part of the disclosure as though
they were explicitly set forth. This includes ranges that can be
formed that do or do not include a finite upper and/or lower
boundary. Accordingly, a person of ordinary skill in the art most
closely related to a particular range, ratio or range of ratios
will appreciate that such values are unambiguously derivable from
the data presented herein.
VI. ILLUSTRATIVE BENEFITS FOR THE PRESENT INVENTION
[0508] A non-exhaustive description of certain advantages of the
present invention over the prior art is described below. For
example, one goal of the present invention was to develop an
opioid/API formulation, such as an oxycodone/acetaminophen
formulation, that has, among other things, the following
characteristics: [0509] Rapid onset of analgesia (e.g., within
approximately 30 minutes); [0510] Extended duration of analgesia
for 12 hours; [0511] Use in the treatment of acute pain; [0512]
Administration of the dosage form without regard to food; [0513]
Acetaminophen absorption primarily in a patient's upper
gastrointestinal tract (upper part of small intestine, e.g.,
duodenum, jejunum), where acetaminophen is best absorbed; [0514]
Prolonged retention of the dosage form in the stomach; [0515]
Obtain the optimal amount and release of oxycodone in the dosage
form in order to prevent inhibition of gastric emptying; [0516]
Minimize oxycodone's effect on gastric emptying, which can blunt
acetaminophen's absorption, by finding the desirable dosing splits
of each agent; [0517] Achieve concentrations of acetaminophen in
the latter part of the dosing cycle that are comparable to pre-dose
concentrations of acetaminophen from immediate-release tablets (in
a multiple-dose setting), allowing a patient's glutathione synthase
enzyme cycle to replenish its levels of glutathione to avoid the
formation of toxic intermediates with subsequent or concomitant
doses of acetaminophen; and [0518] Formulate an
acetaminophen/oxycodone product that achieves acute and prolonged
analgesia with low amounts of acetaminophen and oxycodone.
[0519] While these characteristics provided a general road map for
the development work, several of these characteristics appeared to
be irreconcilable. For example, administration of the dosage form
to patients without regard to food was a very important
characteristic, as patients suffering from acute pain often are
unable to eat and retain food. Yet, in order to achieve prolonged
retention of the dosage form in the stomach, one of skill in the
art would administer the dosage form with food because the presence
of food in the stomach decreases the stomach's migrating motor
complex or "housekeeping wave."
[0520] The "housekeeping wave" is a distinct pattern of cyclic
activity observed in gastrointestinal smooth muscle during the
periods between meals. The cycle recurs every 1.5 to 2 hours and
consists of 4 phases: (1) a period of smooth muscle quiescence
lasting 45 to 60 minutes, during which time there are very minimal
stomach contractions, if any; (2) a period of roughly 30 minutes in
which peristaltic contractions occur and progressively increase in
frequency, (3) a period lasting 5 to 15 minutes in which rapid,
evenly spaced peristaltic contractions occur, and the pylorus
remains open, allowing any indigestible particles to pass into the
small intestine; and (4) a short period of transition between the
barrage of contractions in phase 3 and the inactivity of phase
1.
[0521] So, in the absence of food, strong peristaltic waves would
force the dosage form out of the stomach and into the small
intestine within approximately 1.5 to 2 hours. Therefore, the
dosage form would be unable to gradually release acetaminophen from
the stomach into a patient's upper gastrointestinal tract, where
acetaminophen is best absorbed, over a prolonged period of time
(e.g., greater than 2 hours).
[0522] On the other hand, in the presence of food, a rapid and
distinct change in the motor pattern of the upper gastrointestinal
tract occurs. The change is observed almost simultaneously upon the
ingestion of food at all sites along the gastrointestinal tract.
For example, a peristaltic contraction originates in the
mid-stomach as a shallow similar to those of a housekeeping wave,
but with about half the amplitude. At the start of the contraction,
the pylorus is open, allowing liquids and small particles to leave
the stomach and enter the small intestine. However, the pylorus
constricts as the contraction continues, producing a mass
contraction (termed a terminal antral contraction). This mass
contraction hits the closed pylorus, and this contact forcefully
sends the solid particles back through the constricted antral ring
producing a shearing effect, and fragmenting the solid particles.
This pattern of activity goes on for several hours, causing larger
particles to be retained in the stomach for about 4 to 6 hours.
Thus, gastric emptying is very different in a fasted state versus a
fed state, which can significantly impact the absorption site of a
dosage form.
[0523] As illustrated above, in the development of the improved
opioid/API formulations, the inventors had to balance several,
often conflicting variables. Whether the formulation could be
administered in a fed state versus a fasted state was just one of
those variables. As shown in Table A below, there were several
characteristics that were at odds, or in tension with, with each
other in the development process.
TABLE-US-00004 TABLE A Targeted Characteristics One Desired Another
Desired Characteristic Characteristic Rapid onset of analgesia In
tension with . . . Extended duration of (e.g., within analgesia for
12 hours approximately 30 minutes) Oxycodone/ In tension with . . .
Oxycodone known to affect acetaminophen gastric emptying altering
the combination product absorption of acetaminophen Acute pain
indication In tension with . . . Extended-release formulation
Administration of the In tension with . . . Prolonged retention of
the dosage form without dosage form in the stomach, regard to food
which requires food Achieve low plasma In tension with . . . Need
sufficient pain relief concentrations of throughout the entire
dosing acetaminophen cycle in the latter part of the dosing cycle
Need therapeutically In tension with . . . Need to lessen the
effects effective doses of caused by oxycodone on oxycodone gastric
emptying Lower amounts of In tension with . . . Maintenance of
adequate oxycodone and pain relief over the entire acetaminophen
dosing cycle (e.g., avoid breakthrough pain in the 8- to 12-hour
timeframe)
[0524] In light of the inherent tension between these targeted
characteristics, several road blocks had to be overcome in the
development process. Further, the inventors recognized that it
would likely not be able to formulate a dosage form that possessed
all of the target characteristics (e.g., the dosage form would have
to be administered with food).
[0525] Yet, as a result of the amounts of oxycodone and
acetaminophen in the IR and ER portions, the inventors were able to
develop a formulation with all of the targeted characteristics.
However, this result was unexpected by one skilled in the art.
Indeed, during the development work, the inventors were informed by
several FDA consultants and physicians specializing in the
treatment of pain, that formulations like the ones disclosed
herein, would not be effective in the treatment of acute pain.
Specifically, these consultants were concerned that the lower
amounts of oxycodone in the IR and ER portions would not provide a
patient with adequate pain relief (i.e., be subtherapeutic).
[0526] Further, one of the goals of the development work was to
develop a formulation that would provide a patient suffering from
acute pain with 12 hours of adequate pain relief. One skilled in
the art would realize that decreasing the amounts of oxycodone in
the IR and ER layers from the amounts disclosed in the art would
not provide a longer period of pain relief, and would likely result
in break-through pain. One skilled in the art would also realize
that lower doses of oxycodone in the IR portion would increase the
time it takes for a patient to achieve the maximum plasma
concentration for oxycodone, which would be undesirable in the
treatment of acute pain. Thus, in developing an effective 12-hour,
extended-release formulation for the treatment of acute pain, the
skilled person would conclude that he or she must increase the
amount of oxycodone in the formulations disclosed in the art, not
decrease it. Accordingly, one skilled in the art would not take the
teaching of the art and lower the amounts of oxycodone in the IR
and ER layers based on their teachings.
[0527] In fact, during the development of the formulations
disclosed herein, the inventors actually performed pharmacokinetic
studies on dogs, in which it varied the amounts of oxycodone in the
IR and ER layers. They then took the dog pharmacokinetic data and
used it to stimulate the corresponding human pharmacokinetic data.
They performed these tests to assist them in determining the
amounts of oxycodone and acetaminophen that would be required to
achieve the target pharmacokinetic parameters.
[0528] As illustrated in FIG. 106, those studies showed that
formulations comprising (1) 3 mg, or 20% of the oxycodone in the IR
layer, and 12 mg, or 80% of the oxycodone in the ER layer, and (2)
0 mg, or 0% of the oxycodone in the IR layer, and 15 mg, or 100% of
the oxycodone in the ER layer, did not provide sufficient blood
levels over the dosing interval to anticipate that a patient would
receive adequate pain relief.
[0529] The results shown in FIG. 106 indicate that these
formulations would be subtherapeutic. As a result, this data
confirms that one of skill in the art would not decrease the dose
of oxycodone, but rather, would believe that the dose must be
increased in order to obtain adequate pain relief. Consequently,
one skilled in the art would not have lowered the dose of oxycodone
based on the teachings of the art, as FIG. 106 shows that lower
doses of oxycodone would not provide patients with adequate pain
relief.
[0530] Yet, the inventors surprisingly found that it was able to
formulate an extended-release oxycodone/acetaminophen formulation
with all of the desired characteristics set forth above and with
lower amounts of oxycodone. Indeed, they developed improved
extended-release oxycodone/acetaminophen formulations that possess
the following unexpected characteristics: (1) the formulations may
be administered without regard to food; (2) the formulations
achieve the desired pharmacokinetic parameters, such as, a rapid
onset of analgesia, an extended duration of pain relief, and low
plasma concentrations of acetaminophen in the latter part of the
dosing cycle; and (3) the formulations provide sufficient acute
pain relief.
[0531] These unexpected characteristics are a result of the unique
formulations disclosed herein. For example, the improved
oxycodone/acetaminophen formulations have optimal amounts of
oxycodone and acetaminophen in the IR layer(s) and the ER layer(s).
Indeed, in one representative example, the IR layer(s) comprises
about 1.5 mg to about 4.0 mg of oxycodone and about 125 mg to about
325 mg of acetaminophen, and the ER layer(s) comprises about 4.5 mg
to about 6.5 mg of oxycodone and about 125 mg to about 325 mg of
acetaminophen. While the specific mechanism of action is not known,
these "splits" or amounts of oxycodone and acetaminophen in the
IR/ER layers have several positive and unpredictable benefits.
[0532] First, the "split" of oxycodone between the IR and ER layers
allows the formulations disclosed herein to be administered without
regard to food. Indeed, these formulations allow an optimal amount
of oxycodone to be released early on in the dosing cycle. Once
absorbed, the oxycodone interacts with receptors in the upper
gastrointestinal tract, delaying gastric emptying. The delay in
gastric emptying caused by the amount and release of oxycodone from
the dosage form allows the dosage form to be retained in the
stomach--even in a fasted state. This results in prolonged
retention of the dosage form in the stomach, allowing the
acetaminophen to be slowly released from the dosage form and
optimally absorbed in a patient's upper gastrointestinal tract,
where I believe it is best absorbed. Consequently, it was observed
that the amount and release of oxycodone is unexpectedly just
enough to slow down the stomach (like food) without causing severe
inhibition of gastric emptying, which can often be seen when higher
doses of oxycodone are administered to a patient. Observing these
effects with the first dose is also remarkable and desirable for
treating acute pain.
[0533] The observation that the formulations disclosed herein can
be administered without regard to food was surprising, but also
remarkable as this effect occurs at the very first dose of
administration. By way of example, many formulations have effects
that can only be seen after the patient has been administered three
to five doses of the formulation and has reached "steady state"
plasma concentrations of the drug. However, for the formulations
disclosed herein, a patient does not have to achieve a steady state
plasma concentration for oxycodone to exhibit a lack of food
effect. This is highly beneficial to the patient, and also critical
to the formulations disclosed herein, which treat acute pain and
require an early onset of action to be effective.
[0534] In essence, at the amounts disclosed herein, the effect of
oxycodone on the stomach resembles the effect that food has on the
stomach from the initial dose. Thus, there is no need for a patient
to take the improved oxycodone/acetaminophen formulations with food
in order to achieve the ideal absorption of acetaminophen in the
upper gastrointestinal tract. This freedom provides a significant
clinical benefit to patients in need of pain relief as they often
are unable to eat and/or retain food.
[0535] This result, however, was surprising in view of the teaching
of the art. For instance, the art specifically teaches that the
dosage forms disclosed herein must be taken with food. See, e.g.,
U.S. Patent Publication No. 2010/0015222 ("Han") at 56, 89, 90,
118, 126, 181-82, 238-40, and 244. For example, Han provides that
"[i]t has been determined that once the fed mode [i.e., `the
presence of food in the stomach`] has been induced, larger
particles are retained in the stomach for a longer period of time
than smaller particles. Thus, the fed mode is typically induced in
a patient by the presence of food in the stomach." Id. at 89. Han
also provides that "dosage forms provide controlled delivery of
acetaminophen, and an opioid analgesic to the upper GI tract by a
polymer matrix that swells unrestrained dimensionally, and is
retained in the stomach when taken with food, i.e., in the fed
mode." Id. at 118. Nevertheless, as explained above, the inventors
surprisingly discovered that the claimed amounts of oxycodone in
the IR/ER layers and their release into gastric fluids are all that
is needed to retain the dosage form in the stomach.
[0536] Second, the "splits" of oxycodone and acetaminophen between
the IR and ER layers allows the formulations disclosed herein to
achieve the desired pharmacokinetic parameters. For instance, the
splits produce (1) a rapid onset of analgesia (e.g., within
approximately 30 minutes), which includes a T.sub.max and a
C.sub.max for acetaminophen that is comparable to an
immediate-release acetaminophen product; (2) low plasma
concentrations of acetaminophen in the latter part of the dosing
cycle; and (3) an extended duration of analgesia for 12 hours.
[0537] As explained above, the formulations disclosed herein
achieve a rapid onset of analgesia (e.g., within approximately 30
minutes). Further, these improved extended-release formulations
also achieve a T.sub.max and a C.sub.max of acetaminophen that is
comparable to an immediate-release acetaminophen product. These
results were unexpected for a few reasons.
[0538] In general, extended-release formulations often have a
longer T.sub.max (i.e., the time after administration of a drug
when the maximum plasma concentration, or C.sub.max, is reached in
a patient) in order to provide sufficient pain relief over the
entire dosing interval (e.g., 12 hours). It is also well
established that opioids, like oxycodone, blunt the C.sub.max of
acetaminophen when the two active ingredients are administered
together. Yet, the formulations disclosed herein surprisingly
provide a patient with an early onset of analgesia and a C.sub.max
of acetaminophen that is not affected by the amount of oxycodone
that is present in the formulation.
[0539] Moreover, the absorption of the acetaminophen is complete in
about 8 to about 10 hours. So, for at least one half life of
acetaminophen, the blood supply reaching the patient's liver via
the portal vein contains no additional amounts of acetaminophen
beyond the amounts present in the patient's circulation. As a
result, the concentrations of acetaminophen in the latter part of
the dosing interval are surprisingly comparable to pre-dose
concentrations of acetaminophen seen with immediate release tablets
in a multiple dose setting. This allows the patient's glutathione
synthase enzyme cycle (i.e., the cycle that metabolizes
acetaminophen) to replenish his/her levels of glutathione to avoid
the formation of toxic intermediates with subsequent or concomitant
doses of acetaminophen.
[0540] Further, even though the plasma concentration of
acetaminophen falls at the latter end of the dosing cycle, the
formulations disclosed herein provide a patient with 12 hours of
analgesia. This extended duration of pain relief is a direct result
of the amounts of oxycodone and acetaminophen between the IR and ER
layers, and the differing patterns of release of these two drugs.
Particularly, the formulations were designed to have acetaminophen
and oxycodone work together to provide pain relief in a
complimentary way by taking advantage of their differing
solubilities, mechanisms of action, and pharmacodynamic responses.
The formulations were also designed to try and take advantage of
the known synergy that can occur with the "combination of an
optimum dose of acetaminophen and oxycodone." See Gammaitoni et
al., Effectiveness and Safety of New Oxycodone/Acetaminophen
Formulations With Reduced Acetaminophen for the Treatment of Low
Back Pain, Pain Medicine, Vol. 4, No. 1, at 28 (2003). Thus, the
pharmacokinetic profiles of the oxycodone and the acetaminophen
were not designed to be identical. See FIG. 107. Rather, as a
result of the splits, the pharmacokinetic profiles of oxycodone and
acetaminophen were designed to be offset--capitalizing on the
different mechanisms of action and solubilities of the two active
ingredients.
[0541] Accordingly, as illustrated by the pharmacokinetic curves
set forth in FIG. 107 above, a patient who is administered an
improved oxycodone/acetaminophen formulation disclosed herein
initially experiences a rapid onset of analgesia with the
acetaminophen contributing a larger share of relief. However, at
the end of the dosing cycle, the patient experiences prolonged
analgesia with the oxycodone contributing a larger share of relief.
Consequently, the optimal amounts of oxycodone and acetaminophen
between the IR and ER layers, and the differing patterns of release
of these two drugs, provide a patient with immediate relief and
effective 12-hour pain relief.
[0542] In contrast, and as explained above, one skilled in the art
would not lower the amounts of oxycodone based on the teachings of
the art, in an attempt to provide 12 hours of pain relief. Rather,
the skilled person would increase the amount of oxycodone an
attempt to achieve pain relief over a 12-hour period.
[0543] The offset pharmacokinetic curves for oxycodone and
acetaminophen resulting from the "splits" of those drugs in the IR
and ER layers allows the extended-release formulations disclosed
herein to be used in the treatment of acute pain. This is
surprising as extended-release formulations typically cannot
provide a patient with adequate pain relief early on and throughout
the first dosing cycle. In fact, in inventors are not aware of any
other extended-release opioid/acetaminophen formulation that is
approved by the U.S. Food and Drug Administration for the treatment
of acute pain.
[0544] However, as explained above and illustrated in the
pharmacokinetic data presented in FIG. 107, the extended-release
formulations disclosed herein surprisingly provide a patient in
need thereof with a rapid onset of analgesia and an extended
duration of analgesia of 12 hours.
[0545] Accordingly, the formulations disclosed herein yield several
unexpected results that are not taught or disclosed by the
teachings of the art.
[0546] As presented in Table B below, the extended-release
formulations of the present invention also exhibit a lower
incidence of treatment-emergent adverse events (TEAE) as compared
to the commercially-available immediate release OC/APAP.
TABLE-US-00005 TABLE B Comparison of TEAE between the Present
Invention and a Commercially-Available Immediate Release
Oxycodone/Acetaminophen Product ER OC/APAP Commercially- Disclosed
Herein Available (See Chart No. 1) IR OC/APAP 30/1,300 15/650
15/650 30/1,300 System Organ Class (n = 202) (n = 94) (n = 185) (n
= 67) Preferred Term (%) (%) (%) (%) Gastrointestinal Disorders
Constipation 0 1.1 0.5 0 Nausea 28.7 26.6 30.3 49.3 Vomiting 17.3
4.3 11.4 28.4 Nervous System Disorders Dizziness 13.4 14.9 11.9
22.4 Somnolence 9.9 10.6 6.5 19.4
[0547] Having described the invention in detail, it will be
apparent that modifications and variations are possible without
departing from the scope of the invention defined in the appended
claims.
EXAMPLES
[0548] The following examples are included to demonstrate certain
embodiments of the invention. Those of skill in the art should,
however, in light of the present disclosure, appreciate that
modifications can be made in the specific embodiments that are
disclosed and still obtain a like or similar result without
departing from the spirit and scope of the invention, therefore all
matter set forth is to be interpreted as illustrative and not in a
limiting sense.
Example 1
In Vitro Dissolution of Controlled-Release Bilayer Tablets
[0549] Controlled-release bilayer tablets were prepared containing
15 mg of oxycodone and 500 mg of acetaminophen (APAP), or 30 mg of
oxycodone and 500 mg APAP. (See selected examples from Chart No.
2.) The ER layer contained 75% of the total amount of oxycodone in
the tablet, 50% of the total amount of APAP in the tablet, and
either 35% w/w POLYOX.RTM. 1105 (for fast release), 45% w/w
POLYOX.RTM. 1105 (for medium release), or 45% w/w POLYOX.RTM. N60K
(for slow release). The IR layer contained 25% of the total amount
of oxycodone in the tablet and 50% of the total amount of APAP in
the tablet.
[0550] Dissolution profiles for the three above-described
compositions were determined in USP Type II apparatus. Six tablets
of each composition were weighed, placed in a sinker, and dropped
into an equilibrated dissolution bath vessel that contained 900 mL
of (helium sparged) 0.1 N HCl that was heated to 37.degree.
C..+-.0.5.degree. C. The mixture was stirred at 150.+-.6 rpm and
the temperature was maintained at 37.degree. C..+-.0.5.degree. C.
for 12 hr. The bath vessel was covered with a low evaporation
vessel cover. Samples (5 mL) were removed at 0.25, 0.5, 1, 2, 4, 6,
8, and 12 hours. Each sample was filtered through a 0.45 .mu.m
filter and analyzed by HPLC using standard procedures.
[0551] The cumulative release of oxycodone and APAP from 15 mg
oxycodone/500 mg APAP tablets is presented in Table 1. Table 2
presents the cumulative release of oxycodone and APAP from 30 mg
oxycodone/500 mg APAP (30/500) tablets. FIG. 1 presents the release
profile of oxycodone from the 15/500 and 30/500 tablets. The
dissolution profile of APAP from the 15/500 and 30/500 tablets is
shown in FIG. 2. The release of oxycodone and APAP from the fast
release and medium release tablets was essentially linear during
the first half of the 12 hour time period but then plateaued during
the last half of the 12 hour time period. The release of oxycodone
and APAP from the slow release tablets was essentially linear
during the entire 12 hour time period.
TABLE-US-00006 TABLE 1 Cumulative Release - 15 mg oxycodone/500 mg
APAP Tablets Oxycodone (%) APAP (%) Time (hr) Fast Medium Slow Fast
Medium Slow 0.25 27.56 25.70 25.68 54.78 53.06 53.01 0.5 34.33
31.31 30.39 57.55 55.73 54.89 1.0 -- 40.85 37.81 -- 60.03 58.03 2.0
59.88 55.67 49.50 71.42 68.16 63.27 4.0 83.46 77.94 67.43 86.17
81.55 72.31 6.0 97.48 92.12 80.53 96.19 91.62 79.97 8.0 101.26
99.26 90.20 100.16 96.96 86.06 12.0 101.57 101.23 99.36 100.10
99.16 94.41
TABLE-US-00007 TABLE 2 Cumulative Release - 30 mg oxycodone/500 mg
APAP Tablets Oxycodone (%) APAP (%) Time (hr) Fast Medium Slow Fast
Medium Slow 0.25 31.65 30.27 29.78 54.17 52.97 52.97 0.5 37.55
35.91 34.42 56.96 55.64 54.97 1.0 47.18 45.21 41.12 61.81 60.19
58.15 2.0 62.51 59.63 52.40 70.60 68.04 63.61 4.0 84.72 80.44 70.01
85.28 81.56 73.04 6.0 96.97 93.98 82.49 94.57 91.42 80.94 8.0
100.23 99.63 91.78 97.91 96.48 87.26 12.0 100.57 101.13 99.60 98.09
98.14 95.25
[0552] The cumulative in vitro release of oxycodone and APAP from
7.5 mg oxycodone/325 mg APAP medium release tablets is presented in
Table 3. The ER layer of these tablets contained 5.625 mg of
oxycodone, 162.5 mg of APAP, and 45% (w/w) POLYOX.RTM. 1105, and
the IR layer contained 1.875 mg of oxycodone and 162.5 mg of APAP.
(See selected example from Chart 1.) The dissolution profile was
determined essentially as described above, except that samples were
collected at 0.08 hour (.about.5 min) in addition to the later time
points.
TABLE-US-00008 TABLE 3 Cumulative Release 7.5 mg oxycodone/ 325 mg
APAP Tablets Oxycodone (%) APAP (%) Time Mean % RSD Mean % RSD (hr)
(%) (6) (%) (%) 0.08 26.6 4.3 49.0 3.4 0.25 31.5 4.2 51.3 3.1 0.5
37.5 2.7 53.8 2.9 1.0 45.9 1.6 58.2 2.5 2.0 60.1 1.7 66.0 2.3 4.0
81.4 1.1 78.7 1.7 6.0 95.4 1.4 88.4 1.9 8.0 101.8 0.9 93.9 1.4 12.0
103.2 1.2 94.9 1.1
[0553] FIG. 3 and FIG. 4 present the percentage of oxycodone and
APAP, respectively, released from two different lots of 7.5/325
tablets as compared to 15/650 tablets (see Example 27 for the
dissolution data of the 15 mg oxycodone/650 acetaminophen tablets).
The dissolution profiles were similar among all the tablets.
[0554] The release of oxycodone and APAP from each layer was
analyzed by determining the calculated release from the ER layer
and actual release from the total composition. For this, the
tablets contained 7.5 mg of oxycodone HCl and 325 mg of APAP (i.e.,
the ER layer contained 5.625 mg of oxycodone HCl, 162.5 mg of APAP,
and 45% (w/w) POLYOX.RTM. 1105; and the IR layer contained 1.875 mg
of oxycodone HCl and 162.5 mg of APAP). The dissolution profile was
determined essentially as described above. The calculated
cumulative release of oxycodone HCl from the ER layer and the total
tablet is presented in Table 4, and the calculated cumulative
release of APAP from the ER layer and the total tablet is presented
in Table 5. These data show that essentially all of the 1.875 mg of
oxycodone HCl in the IR layer was released within about 5 minutes
and essentially all of the 162.5 mg of APAP in the IR layer was
released within about 15 minutes.
TABLE-US-00009 TABLE 4 Split Release of Oxycodone 7.5 mg
oxycodone/325 mg APAP Tablets Time Total Total ER ER (hr) (%) (mg)
(%) (mg) 0.08 26.6 2.00 2.1 0.12 0.25 31.5 2.36 8.7 0.49 0.5 37.5
2.81 16.7 0.94 1.0 45.9 3.44 27.9 1.57 2.0 60.1 4.51 46.8 2.63 4.0
81.4 6.11 75.2 4.23 6.0 95.4 7.16 93.9 5.28 8.0 101.8 7.64 102.4
5.76 12.0 103.2 7.74 104.3 5.87
TABLE-US-00010 TABLE 5 Split Release of APAP 7.5 mg oxycodone/325
mg APAP Tablets Time Total Total ER ER (hr) (%) (mg) (%) (mg) 0.08
49.0 159.25 0.0 0.00 0.25 51.3 166.73 2.6 4.22 0.5 53.8 174.85 7.6
12.35 1.0 58.2 189.15 16.4 26.65 2.0 66.0 214.50 32.0 52.00 4.0
78.7 255.78 57.4 93.28 6.0 88.4 287.30 76.8 124.80 8.0 93.9 305.18
87.8 142.68 12.0 94.9 308.43 89.8 145.93
Example 2
Clinical Pharmacokinetic Analysis of Controlled-Release 15 mg
Oxycodone/500 mg Acetaminophen Bilayer Tablets--Single Dose
[0555] An open-label, single dose, four-period crossover study was
conducted to evaluate the pharmacokinetics (PK) and bioavailability
of three controlled-release bilayer tablets comprising 15 mg
oxycodone (OC) and 500 mg APAP as compared to a commercially
available immediate-release tablet containing 7.5 mg oxycodone/325
mg acetaminophen. The three controlled release formulations--fast,
medium, and slow--are described above. (See selected examples from
Chart No. 2.) One tablet of each of the controlled-release bilayer
formulations was administered to the test subjects under fed
conditions. One tablet of the commercially available
immediate-release tablet containing 7.5 mg oxycodone/325 mg
acetaminophen was administered every 6 hours (Q6 h) for two doses
under fed conditions. The test subjects were about 40 normal,
healthy male subjects between 21-45 years of age.
[0556] Subjects were randomly assigned to Treatments A, B, C, and D
using a four-period, eight-sequence, crossover design as follows:
[0557] Treatment A: One (1) tablet of 15 mg OC/500 mg APAP, Fast
Release administered orally under fed conditions. [0558] Treatment
B: One (1) tablet of 15 mg OC/500 mg APAP, Medium Release
administered orally under fed conditions. [0559] Treatment C: One
(1) tablet of 15 mg OC/500 mg APAP, Slow Release administered
orally under fed conditions. [0560] Treatment D: One (1) tablet of
a commercially available immediate-release tablet containing 7.5 mg
oxycodone/325 mg administered orally Q6 h for two (2) doses under
fed conditions.
[0561] The crossover design allowed for within-subject comparisons
among the test formulations with differing release profiles.
Subjects received each of the study drug treatments (A-D) separated
by at least a 7-day interval between the start of each period at
Hour 0. During each period, subjects remained in the clinical
facility from the time of check-in (on the day prior to dosing)
until discharge on Day 3 (after the 48 hour blood draw).
[0562] Physical examinations, electrocardiograms and clinical
laboratory tests were performed at screening and at the conclusion
of the study (or early termination). Vital sign measurements
(including pulse oximetry) and adverse events were monitored during
the study. Subjects were administered a 50 mg naltrexone tablet 12
hours prior to Hour 0 dosing, at Hour 0, and 12 hours post-dose to
block the effects and potential risks of oxycodone. After a 10 hour
overnight fast, subjects were served a standardized FDA high-fat
breakfast to be consumed in 30 minutes or less prior to Hour 0
dosing for the first oral dosage. All subjects in each period were
served a standardized meal to be consumed in 30 minutes or less
prior to Hour 6. Only subjects randomized to Treatment D were
administered the second oral dosage of the commercially available
immediate-release tablet containing 7.5 mg oxycodone/325 mg
acetaminophen at Hour 6 in each period.
[0563] Blood was drawn at designated times for PK analysis. Samples
(6 mL in pre-chilled vacuum blood collection tubes, containing
K2EDTA as the anticoagulant) were taken pre-dose (up to 60 minutes
prior to dose), 10 min, 20 min, 30 min, 40 min and 1, 2, 3, 4, 5,
6, 6.5, 7, 8, 9, 10, 12, 16, 18, 20, 24, 36 and 48 hours post-dose.
The collected plasma samples were analyzed for the active
pharmaceutical ingredients (APIs), i.e., oxycodone and
acetaminophen, using validated liquid chromatography/tandem mass
spectrometry (LC-MS/MS) assays.
[0564] The following PK parameters were calculated for oxycodone
and acetaminophen using standard non-compartmental methods: [0565]
area under the plasma concentration curve to last quantifiable
concentration AUC.sub.(0-t) [0566] area under the plasma
concentration curve to infinite time AUC.sub.(0-inf) [0567] maximum
observed plasma concentration (C.sub.max) [0568] time observed
maximum plasma concentration (t.sub.max) [0569] lag time
(t.sub.lag) [0570] apparent first-order terminal elimination rate
constant (k.sub.el) [0571] apparent plasma terminal elimination
half-life (t.sub.1/2)
[0572] Parametric general linear model (GLM) methodology was used
in the analysis of all pharmacokinetic parameters. The SAS GLM
procedure was used to perform analysis of variance (ANOVA) on each
pharmacokinetic parameter with sequence, treatment, period, and
subjects nested within sequences, as sources of variation. For each
formulation, least squares means and the associated standard errors
were obtained using the LSMEANS option. All treatment pairwise
comparisons were performed, without adjustment for multiplicity.
AUC and C.sub.max were dose-adjusted for comparative purposes for
acetaminophen and the commercially available immediate-release
tablet containing 7.5 mg oxycodone/325 mg acetaminophen.
[0573] The pharmacokinetic data for oxycodone and APAP are
presented in Tables 6-8 and 9-11, respectively.
TABLE-US-00011 TABLE 6 Oxycodone Pharmacokinetics (15/500)
Commercially available Fast Release Formulation immediate- Mean LSM
90% CI release tablet Parameter (% CV) Ratio Lower Upper Mean (%
CV) C.sub.max (ng/mL) 18.803 82.92 78.02 88.12 22.428 (21) (20)
C.sub.1 hr (ng/mL) 6.891 72.79 49.02 108.1 10.226 (77) (65) C.sub.2
hr.sup.a (ng/mL) 12.355 80.74 71.2 91.56 14.94 (32) (26)
AUC.sub.0-t 209.949 89.73 86.52 93.06 229.788 (ng hr/mL) (26) (22)
AUC.sub.0-inf 211.8 89.95 86.77 93..24 231.421 (ng hr/mL) (25) (22)
AUC.sub.0-1 hr 2.565 61.32 37.64 99.92 4.334 (ng hr/mL) (104) (80)
AUC.sub.0-2 hr.sup.b 12.189 70.16 55.97 87.95 16.917 (ng hr/mL)
(53) (46) AUC.sub.0-4 hr.sup.c 41.3 88.76 80.61 97.73 45.699 (ng
hr/mL) (29) (24) T.sub.max (hr) 4.954 na na na 7.954 (34) (22)
T.sub.lag (hr) 0.31 na na na 0.219 (68) (77) T.sub.1/2 (hr) 4.584
na na na 4.495 (17) (14) K.sub.el (1/hr) 0.155 na na na 0.157 (16)
(13) .sup.aConcentration at the median T.sub.max for
commercially-available immediate release tablet .sup.bAUC from zero
the median T.sub.max for commercially-available immediate release
tablet .sup.cAUC from the zero to the median T.sub.max + 2 SD for
commercially-available immediate release tablet
TABLE-US-00012 TABLE 7 Oxycodone Pharmacokinetics (15/500)
Commercially- available immediate release Medium Release
Formulation tablet Mean LSM 90% CI Mean Parameter (%CV) Ratio Lower
Upper (%CV) C.sub.max (ng/mL) 18.266 80.87 76.09 85.95 22.428 (25)
(20) C.sub.1 hr (ng/mL) 7.364 67.62 45.75 99.95 10.226 (81) (65)
C.sub.2 hr.sup.a (ng/mL) 12.388 79.04 69.69 89.64 14.94 (45) (26)
AUC.sub.0-t 217.188 94.19 90.82 97.68 229.788 (ng hr/mL) (23) (22)
AUC.sub.0-inf 218.545 94.09 90.77 97.54 231.421 (ng hr/mL) (23)
(22) AUC.sub.0-1 hr 3.248 64.69 39.93 104.8 4.334 (ng hr/mL) (118)
(80) AUC.sub.0-2 hr.sup.b 13.124 71.74 57.22 89.96 16.917 (ng
hr/mL) (70) (46) AUC.sub.0-4 hr.sup.c 42.101 88.61 80.47 97.58
45.699 (ng hr/mL) (43) (24) T.sub.max (hr) 5.31 na na na 7.954 (38)
(22) T.sub.lag (hr) 0.264 na na na 0.219 (64) (77) T.sub.1/2 (hr)
4.557 na na na 4.495 (16) (14) K.sub.el (1/hr) 0.156 na na na 0.157
(16) (13) .sup.aConcentration at the median T.sub.max for
commercially-available immediate release tablet .sup.bAUC from zero
the median T.sub.max for commercially-available immediate release
tablet .sup.cAUC from the zero to the median T.sub.max + 2 SD for
commercially-available immediate release tablet
TABLE-US-00013 TABLE 8 Oxycodone Pharmacokinetics (15/500)
Commercially- available immediate release Slow Release Formulation
tablet Mean LSM 90% CI Mean Parameter (% CV) Ratio Lower Upper (%
CV) C.sub.max (ng/mL) 17.403 76.75 72.21 81.58 22.428 (25) (20)
C.sub.1 hr (ng/mL) 7.601 69.63 47.08 102.97 10.226 (79) (65)
C.sub.2 hr.sup.a (ng/mL) 11.237 73.55 64.84 83.43 14.94 (39) (26)
AUC.sub.0-t 222.096 95.62 92.2 99.18 229.788 (ng hr/mL) (25) (22)
AUC.sub.0-inf 223.553 95.61 92.22 99.11 231.421 (ng hr/mL) (25)
(22) AUC.sub.0-1 hr 2.893 57.34 35.37 92.95 4.334 (ng hr/mL) (112)
(80) AUC.sub.0-2 hr.sup.b 12.312 68.63 54.72 86.08 16.917 (ng
hr/mL) (66) (46) AUC.sub.0-4 hr.sup.c 38.842 83.46 75.78 91.92
45.699 (ng hr/mL) (35) (24) T.sub.max (hr) 5.655 na na na 7.954
(27) (22) T.sub.lag (hr) 0.299 na na na 0.219 (74) (77) T.sub.1/2
(hr) 4.647 na na na 4.495 (19) (14) K.sub.el (1/hr) 0.154 na na na
0.157 (18) (13) .sup.aConcentration at the median T.sub.max for
commercially-available immediate release tablet .sup.bAUC from zero
the median T.sub.max for commercially-available immediate release
tablet .sup.cAUC from the zero to the median T.sub.max + 2 SD for
commercially-available immediate release tablet
TABLE-US-00014 TABLE 9 Acetaminophen Pharmacokinetics (15/500)
Commercially- available immediate release Fast Release Formulation
tablet* Mean LSM 90% CI Mean Parameter (% CV) Ratio Lower Upper (%
CV) C.sub.max (ng/mL) 2612 94.46 87.25 102.26 2721 (26) (22)
C.sub.1 hr (ng/mL) 1627 113.22 84.91 150.98 1516 (66) (58) C.sub.2
hr.sup.a (ng/mL) 2248 118.49 107.61 130.48 1841 (30) (20)
AUC.sub.0-t 21944 98.78 95.91 101.75 21962 (ng hr/mL) (27) (22)
AUC.sub.0-inf 23090 98.73 95.85 101.7 23104 (ng hr/mL) (27) (21)
AUC.sub.0-1 hr 823 105.42 68.75 161.64 814 (ng hr/mL) (96) (82)
AUC.sub.0-2 hr.sup.b 2761 106.73 86.55 131.62 2492 (ng hr/mL) (52)
(47) AUC.sub.0-4 hr.sup.c 7006 119.91 110.42 130.2 5726 (ng hr/mL)
(28) (22) T.sub.max (hr) 2.328 na na na 6.971 (58) (34) T.sub.lag
(hr) 0.276 na na na 0.219 (81) (98) T.sub.1/2 (hr) 5.235 na na na
6.461 (35) (66) K.sub.el (1/hr) 0.145 na na na 0.137 (28) (39)
*Dose Normalized to 500 mg .sup.aConcentration at the median
T.sub.max for commercially-available immediate release tablet
.sup.bAUC from zero the median T.sub.max for commercially-available
immediate release tablet .sup.cAUC from the zero to the median
T.sub.max + 2 SD for commercially-available immediate release
tablet
TABLE-US-00015 TABLE 10 Acetaminophen Pharmacokinetics (15/500)
Commercially- available immediate Medium Release Formulation
release tablet* Mean LSM 90% CI Mean Parameter (% CV) Ratio Lower
Upper (% CV) C.sub.max 2720 99.19 91.61 107.39 2721 (ng/mL) (22)
(22) C.sub.1 hr 1831 121.62 91.51 161.65 1516 (ng/mL) (54) (58)
C.sub.2 hr.sup.a 2170 116.69 105.96 128.51 1841 (ng/mL) (23) (20)
AUC.sub.0-t 22184 100.68 97.74 103.7 21962 (ng hr/mL) (22) (22)
AUC.sub.0-inf 23554 101.39 98.43 104.44 23104 (ng hr/mL) (22) (21)
AUC.sub.0-1 hr 974 124.39 81.52 189.79 814 (ng hr/mL) (85) (82)
AUC.sub.0-2 hr.sup.b 2974 117.9 95.58 145.43 2492 (ng hr/mL) (47)
(47) AUC.sub.0-4 hr.sup.c 7122 123.98 114.17 134.64 5726 (ng hr/mL)
(23) (22) T.sub.max 2.069 na na na 6.971 (hr) (66) (34) T.sub.lag
0.218 na na na 0.219 (hr) (77) (98) T.sub.1/2 5.696 na na na 6.461
(hr) (33) (66) K.sub.el 0.133 na na na 0.137 (1/hr) (29) (39) *Dose
Normalized to 500 mg .sup.aConcentration at the median T.sub.max
for commercially-available immediate release tablet .sup.bAUC from
zero the median T.sub.max for commercially-available immediate
release tablet .sup.cAUC from the zero to the median T.sub.max +
2SD for commercially-available immediate release tablet
TABLE-US-00016 TABLE 11 Acetaminophen Pharmacokinetics (15/500)
Commercially- available immediate Slow Release Formulation release
tablet* Mean LSM 90% CI Mean Parameter (% CV) Ratio Lower Upper (%
CV) C.sub.max 2521 93.6 86.44 101.35 2721 (ng/mL) (18) (22) C.sub.1
hr 1766 126.26 94.96 167.87 1516 (ng/mL) (51) (58) C.sub.2 hr.sup.a
2113 116.18 105.48 127.96 1841 (ng/mL) (18) (20) AUC.sub.0-t 21947
99.61 96.7 102.61 21962 (ng hr/mL) (25) (22) AUC.sub.0-inf 23279
100.47 97.53 103.49 23104 (ng hr/mL) (25) (21) AUC.sub.0-1 hr 872
115.25 75.49 175.95 814 (ng hr/mL) (83) (82) AUC.sub.0-2 hr.sup.b
2811 116.49 94.42 143.73 2492 (ng hr/mL) (43) (47) AUC.sub.0-4
hr.sup.c 6828 120.68 111.11 131.07 5726 (ng hr/mL) (19) (22)
T.sub.max 2.184 na na na 6.971 (hr) (59) (34) T.sub.lag 0.253 na na
na 0.219 (hr) (86) (98) T.sub.1/2 5.366 na na na 6.461 (hr) (32)
(66) K.sub.el 0.141 na na na 0.137 (1/hr) (28) (39) *Dose
Normalized to 500 mg .sup.aConcentration at the median T.sub.max
for commercially-available immediate release tablet .sup.bAUC from
zero the median T.sub.max for commercially-available immediate
release tablet .sup.cAUC from the zero to the median T.sub.max +
2SD for commercially-available immediate release tablet
[0574] The pharmacokinetic parameters for the medium release 15/500
formulation and the commercially-available immediate release tablet
are shown in Table 12.
TABLE-US-00017 TABLE 12 Pharmacokinetic Profile (Mean .+-. SD) of
Oxycodone/APAP versus commercially- available immediate release
tablet (N = 29) C.sub.max AUC.sub.0-t AUC.sub.0-inf T.sub.max
K.sub.el t.sub.1/2 Dosage (ng/mL) ng hr/mL) (ng hr/mL) (hr) (1/hr)
(hr) Oxycodone 15 mg OC/500 mg APAP 18.3 .+-. 4.6 217 .+-. 49.2 219
.+-. 49.5 5.3 .+-. 0.156 .+-. 4.6 .+-. Commercially - 2.0 0.024 0.7
available immediate 22.4 .+-. 4.5* 230 .+-. 49.8 231 .+-. 50.0 8.0
.+-. 0.157 .+-. 4.5 .+-. release tablet (7.5 mg 1.7* 0.020 0.6
OC/325 mg APAP) Acetaminophen 15 mg OC/500 mg APAP 2720 .+-. 608
221184 .+-. 23554 .+-. 2.1 .+-. 0.137 .+-. 5.7 .+-. Commercially -
4804 5234 1.4 0.039 1.9 available immediate 2721 .+-. 584* 21962
.+-. 23104 .+-. 7.0 .+-. 0.137 .+-. 6.5 .+-. release tablet.sup.a
(7.5 mg 4772 4882 2.4* 0.054 4.3 OC/325 mg APAP) *Most values
occurred after the second dose. .sup.aAUC and C.sub.max
dose-normalized to 500 mg for APAP.
[0575] The oxycodone mean plasma concentration as a function of
time after administration of 15/500 tablets is shown in Table 13
and FIG. 5. The APAP mean plasma concentration over time after
administration of 15/500 tablets is shown in Table 14 and FIG.
6.
TABLE-US-00018 TABLE 13 Time Course of Oxycodone Plasma
Concentration (ng/mL) Mean commercially- available Time Mean Mean
Mean immediate (hr) Fast SEM Medium SEM Slow SEM release tablet SEM
0 0 0 0 0 0 0 0 0 0.17 0 0 0.13 0.11 0.06 0.02 0.03 0.03 0.33 0.65
0.29 1.08 0.44 0.93 0.41 1.16 0.36 0.5 2.09 0.55 2.98 0.95 2.55
0.96 4.03 0.9 0.67 3.74 0.91 5.29 1.25 4.15 1.1 7.04 0.93 1 6.89
0.98 7.36 1.11 7.6 1.24 10.23 1.11 2 12.36 0.74 12.39 1.04 11.24
0.73 14.94 0.81 3 14.77 0.82 14.73 0.91 13.35 0.53 14.84 0.62 4
16.33 0.8 16.1 0.82 15.12 0.44 12.95 0.58 5 16.28 0.67 15.89 0.81
15.83 0.41 10.58 0.8 6 17.4 0.72 16.43 0.81 15.76 0.41 9.1 0.67 6.5
16.59 0.64 15.89 0.72 15.22 0.96 10.76 0.7 7 15.28 0.58 14.83 0.69
14.49 1.43 16.84 0.69 8 14.02 0.6 14.29 0.64 13.77 0.85 19.7 0.7 9
13.13 0.57 13.39 0.55 13 0.78 19.08 0.65 10 11.9 0.64 12.52 0.53
11.92 0.68 16.63 0.57 12 8.86 0.6 9.59 0.49 10.04 0.59 10.88
0.53
TABLE-US-00019 TABLE 14 Time Course of Acetaminophen Plasma
Concentration (ng/mL) Mean commer- cially available imme- diately
Time Mean Mean Mean release (hr) Fast SEM Medium SEM Slow SEM
tablet SEM 0 0 0 0 0 0 0 0 0 0.17 31 18 284 151 220 88 107 47 0.33
673 210 751 221 678 197 607 173 0.5 1216 266 1299 275 1133 248 1181
229 0.67 1624 301 1922 301 1647 252 1653 255 1 2116 258 2380 239
2296 217 1971 210 2 2922 160 2821 123 2747 93 2393 90 3 2736 129
2719 90 2636 94 2150 65 4 2643 120 2524 103 2424 110 1717 71 5 2376
112 2246 121 2130 118 1290 59 6 2263 100 2080 143 1965 107 1006 58
6.5 2068 93 1903 126 1774 102 1742 212 7 1830 80 1744 116 1644 98
2749 232 8 1577 81 1573 103 1495 93 2790 114 9 1416 79 1407 88 1330
80 2482 111 10 1286 82 1314 84 1198 71 1968 105 12 1069 89 1131 86
1089 66 1188 82
Example 3
Clinical Pharmacokinetic Analysis of Controlled-Release 30 mg
Oxycodone/500 mg Acetaminophen Bilayer Tablets--Single Dose
[0576] A single dose, four-period crossover study was conducted
essentially as described in Example 2, except the
controlled-release bilayer tablets contained 30 mg oxycodone and
500 mg APAP. (See selected examples from Chart No. 2.) Tables 15-17
and 18-20 present the PK data for oxycodone and APAP, respectively.
The plasma concentrations of oxycodone and APAP are presented in
FIG. 7 and FIG. 8, respectively.
TABLE-US-00020 TABLE 15 Oxycodone Pharmacokinetics (30/500)
Commercially- available immediate Fast Release Formulation release
tablet Mean LSM 90% CI Mean Parameter (% CV) Ratio Lower Upper (%
CV) C.sub.max 39.159 82.17 75.96 88.9 47.597 (ng/mL) (28) (26)
C.sub.1 hr 20.462 77.25 54.37 109.76 25.911 (ng/mL) (74) (67)
C.sub.2 hr.sup.a 28.221 95.18 83.82 108.08 29.579 (ng/mL) (39) (32)
AUC.sub.0-t 393.952 92.84 89.3 96.53 425.978 (ng hr/mL) (30) (29)
AUC.sub.0-inf 396.135 92.4 88.94 95.99 430.196 (ng hr/mL) (29) (29)
AUC.sub.0-1 hr 9.106 71.09 46.05 109.76 11.55 (ng hr/mL) (100) (93)
AUC.sub.0-2 hr.sup.b 33.448 82.59 67.9 100.46 39.295 (ng hr/mL)
(61) (53) AUC.sub.0-4 hr.sup.c 96.47 101.27 91.51 112.06 93.706 (ng
hr/mL) (38) (29) AUC.sub.4 hr-t.sup.d 395.522 92.4 88.95 95.99
429.507 (29) (29) T.sub.max 4.057 na na na 6.948 (hr) (51) (33)
T.sub.lag 0.213 na na na 0.184 (hr) (107) (66) T.sub.1/2 4.398 na
na na 4.32 (hr) (15) (15) K.sub.el 0.161 na na na 0.164 (1/hr) (15)
(16) .sup.aConcentration at the median T.sub.max for
commercially-available immediate release tablet .sup.bAUC from zero
the median T.sub.max for commercially-available immediate release
tablet .sup.cAUC from the zero to the median T.sub.max + 2SD for
commercially-available immediate release tablet
TABLE-US-00021 TABLE 16 Oxycodone Pharmacokinetics (30/500)
Commercially- available immediate Medium Release Formulation
release tablet Mean LSM 90% CI Mean Parameter (% CV) Ratio Lower
Upper (% CV) C.sub.max 36.731 77.14 71.27 83.48 47.597 (ng/mL) (30)
(26) C.sub.1 hr 19.758 86.12 60.48 122.62 25.911 (ng/mL) (70) (67)
C.sub.2 hr.sup.a 27.655 93.53 82.31 106.28 29.579 (ng/mL) (39) (32)
AUC.sub.0-t 396.026 94.17 90.55 97.92 425.978 (ng hr/mL) (29) (29)
AUC.sub.0-inf 398.084 93.68 90.16 97.34 430.196 (ng hr/mL) (29)
(29) AUC.sub.0-1 hr 8.988 93.06 60.12 144.04 11.55 (ng hr/mL) (85)
(93) AUC.sub.0-2 hr.sup.b 32.695 86.02 70.64 104.74 39.295 (ng
hr/mL) (56) (53) AUC.sub.0-4 hr.sup.c 91.998 98.13 88.63 108.65
93.706 (ng hr/mL) (36) (29) AUC.sub.4 hr-t.sup.d 397.436 93.68
90.16 97.34 429.507 (29) (29) T.sub.max 4.523 na na na 6.948 (hr)
(51) (33) T.sub.lag 0.207 na na na 0.184 (hr) (95) (66) T.sub.1/2
4.369 na na na 4.32 (hr) (14) (15) K.sub.el 0.162 na na na 0.164
(1/hr) (14) (16) .sup.aConcentration at the median T.sub.max for
commercially-available immediate release tablet .sup.bAUC from zero
the median T.sub.max for commercially-available immediate release
tablet .sup.cAUC from the zero to the median T.sub.max + 2SD for
commercially-available immediate release tablet
TABLE-US-00022 TABLE 17 Oxycodone Pharmacokinetics (30/500)
Commercially- available immediate Slow Release Formulation release
tablet Mean LSM 90% CI Mean Parameter (% CV) Ratio Lower Upper (%
CV) C.sub.max 32.976 68.96 63.74 74.6 47.597 (ng/mL) (29) (26)
C.sub.1 hr 17.897 73.61 52.01 104.18 25.911 (ng/mL) (74) (67)
C.sub.2 hr.sup.a 23.183 78.42 69.06 89.05 29.579 (ng/mL) (33) (32)
AUC.sub.0-t 399.623 94.5 90.9 98.25 425.978 (ng hr/mL) (26) (29)
AUC.sub.0-inf 401.362 93.88 90.36 97.52 430.196 (ng hr/mL) (26)
(29) AUC.sub.0-1 hr 7.643 69.93 45.52 107.44 11.55 (ng hr/mL) (96)
(93) AUC.sub.0-2 hr.sup.b 28.183 71.58 58.85 87.06 39.295 (ng
hr/mL) (59) (53) AUC.sub.0-4 hr.sup.c 82.171 86.17 77.87 95.35
93.706 (ng hr/mL) (36) (29) AUC.sub.4 hr-t.sup.d 400.56 93.85 90.34
97.49 429.507 (26) (29) T.sub.max 3.96 na na na 6.948 (hr) (48)
(33) T.sub.lag 0.201 na na na 0.184 (hr) (78) (66) T.sub.1/2 4.418
na na na 4.32 (hr) (17) (15) K.sub.el 0.161 na na na 0.164 (1/hr)
(17) (16) .sup.aConcentration at the median T.sub.max for
commercially-available immediate release tablet .sup.bAUC from zero
the median T.sub.max for commercially-available immediate release
tablet .sup.cAUC from the zero to the median T.sub.max + 2SD for
commercially-available immediate release tablet
TABLE-US-00023 TABLE 18 Acetaminophen Pharmacokinetics (30/500)
Commercially- available immediate Fast Release Formulation release
tablet Mean LSM 90% CI Mean Parameter (% CV) Ratio Lower Upper (%
CV) C.sub.max 3138 101.52 91.58 122.53 3085 (ng/mL) (32) (29)
C.sub.1 hr 2163 130.98 101.04 169.78 1777 (ng/mL) (59) (59) C.sub.2
hr.sup.a 2386 125.37 113.22 138.82 1892 (ng/mL) (32) (28)
AUC.sub.0-t 21742 98.53 95.07 102.13 21897 (ng hr/mL) (26) (23)
AUC.sub.0-inf 22798 99.02 95.5 102.66 22881 (ng hr/mL) (26) (23)
AUC.sub.0-1 hr 1260 122.71 85.05 177.03 1005 (ng hr/mL) (85) (80)
AUC.sub.0-2 hr.sup.b 3534 120.52 100.69 144.26 2839 (ng hr/mL) (53)
(48) AUC.sub.0-4 hr.sup.c 8038 130.54 119.98 142.02 6041 (ng hr/mL)
(33) (27) AUC.sub.4 hr-t.sup.d 14707 86.22 82.35 90.27 16720 (32)
(26) T.sub.max 1.908 na na na 5.615 (hr) (69) (54) T.sub.lag 0.236
na na na 0.178 (hr) (106) (90) T.sub.1/2 4.798 na na na 5.3 (hr)
(26) (43) K.sub.el 0.153 na na na 0.152 (1/hr) (25) (36) * Dose
Normalized to 500 mg .sup.aConcentration at the median T.sub.max
for commercially-available immediate release tablet .sup.bAUC from
zero the median T.sub.max for commercially-available immediate
release tablet .sup.cAUC from the zero to the median T.sub.max +
2SD for commercially-available immediate release tablet
TABLE-US-00024 TABLE 19 Acetaminophen Pharmacokinetics (30/500)
Commercially- available immediate Medium Release Formulation
release tablet Mean LSM 90% CI Mean Parameter (% CV) Ratio Lower
Upper (% CV) C.sub.max 2940 93.8 84.57 104.03 3085 (ng/mL) (38)
(29) C.sub.1 hr 2161 139.29 107.29 180.84 1777 (ng/mL) (56) (59)
C.sub.2 hr.sup.a 2349 125.86 113.61 139.44 1892 (ng/mL) (27) (28)
AUC.sub.0-t (ng hr/mL) 21822 99.42 95.9 103.06 21897 (26) (23)
AUC.sub.0-inf (ng hr/mL) 23107 100.76 97.16 104.49 22881 (26) (23)
AUC.sub.0-1 hr (ng hr/mL) 1342 155.89 107.81 225.4 1005 (81) (80)
AUC.sub.0-2 hr.sup.b (ng hr/mL) 3596 129.14 107.79 154.73 2839 (52)
(48) AUC.sub.0-4 hr.sup.c (ng hr/mL) 7880 130.08 119.51 141.59 6041
(32) (27) AUC.sub.4 hr-t.sup.d 15040 88.93 84.92 93.13 16720 (29)
(26) T.sub.max 1.724 na na na 5.615 (hr) (62) (54) T.sub.lag 0.19
na na na 0.178 (hr) (114) (90) T.sub.1/2 6.116 na na na 5.3 (hr)
(63) (43) K.sub.el .0139 na na na 0.152 (1/hr) (37) (36) * Dose
Normalized to 500 mg .sup.aConcentration at the median T.sub.max
for commercially-available immediate release tablet .sup.bAUC from
zero the median T.sub.max for commercially-available immediate
release tablet .sup.cAUC from the zero to the median T.sub.max +
2SD for commercially-available immediate release tablet
TABLE-US-00025 TABLE 20 Acetaminophen Pharmacokinetics (30/500)
Commercially- available immediate Slow Release Formulation release
tablet Mean LSM 90% CI Mean Parameter (% CV) Ratio Lower Upper (%
CV) C.sub.max 2734 88.33 79.68 97.91 3085 (ng/mL) (33) (29) C.sub.1
hr 1989 120.26 93.05 155.44 1777 (ng/mL) (53) (59) C.sub.2 hr.sup.a
2131 112.77 101.84 124.86 1892 (ng/mL) (25) (28) AUC.sub.0-t 21272
97.1 93.68 100.64 21897 (ng hr/mL) (23) (23) AUC.sub.0-inf 22504
98.45 94.95 102.07 22881 (ng hr/mL) (22) (23) AUC.sub.0-1 hr 1092
120.91 84.15 173.72 1005 (ng hr/mL) (76) (80) AUC.sub.0-2 hr.sup.b
3152 112.74 94.19 134.94 2839 (ng hr/mL) (45) (48) AUC.sub.0-4
hr.sup.c 7217 119.31 109.5 129.61 6041 (ng hr/mL) (26) (27)
AUC.sub.4 hr-t.sup.d 15227 90.59 86.52 94.85 16720 (26) (26)
T.sub.max 1.897 na na na 5.615 (hr) (56) (54) T.sub.lag 0.196 na na
na 0.178 (hr) (79) (90) T.sub.1/2 4.843 na na na 5.3 (hr) (27) (43)
K.sub.el 0.152 na na na 0.152 (1/hr) (24) (36) * Dose Normalized to
500 mg .sup.aConcentration at the median T.sub.max for
commercially-available immediate release tablet .sup.bAUC from zero
the median T.sub.max for commercially-available immediate release
tablet .sup.cAUC from the zero to the median T.sub.max + 2SD for
commercially-available immediate release tablet
[0577] The pharmacokinetic parameters for the medium release 30/500
formulation and the commercially-available immediate release tablet
are shown in Table 21.
TABLE-US-00026 TABLE 21 Pharmacokinetic Profile (Mean .+-. SD) of
Oxycodone/APAP versus Commercially-available immediate release
tablet (N = 29) C.sub.max AUC.sub.0-t AUC.sub.0-inf T.sub.max
K.sub.el t.sub.1/2 Dosage (ng/mL) (ng hr/mL) (ng hr/mL) (hr) (1/hr)
(hr) Oxycodone 30 mg OC/500 mg 36.7 .+-. 396 .+-. 116 398 .+-. 115
4.5 .+-. 0.162 .+-. 4.4 .+-. APAP 10.9 2.3 0.023 0.6 Commercially-
47.6 .+-. 426 .+-. 125 430 .+-. 124 6.9 .+-. 0.164 .+-. 4.3 .+-.
available 12.3* 2.3* 0.026 0.6 immediate release tablet.sup.a (7.5
mg OC/325 mg APAP) Acetaminophen 30 mg OC/500 mg 2940 .+-. 21822
.+-. 23107 .+-. 1.7 .+-. 0.139 .+-. 6.1 .+-. APAP 1105 5630 5927
1.1 0.052 3.9 Commercially 3085 .+-. 21897 .+-. 22881 .+-. 5.6 .+-.
0.152 .+-. 5.3 .+-. available- 899* 5125 5362 3.0* 0.055 2.3
immediate release tablet.sup.a (7.5 mg OC/325 mg APAP) *Most values
occurred after the second dose. .sup.aAUC and Cmax dose-normalized
to 30 mg for OC and 500 mg for APAP.
Example 4
Clinical Pharmacokinetic Analysis of Controlled-Release 15 mg
Oxycodone/650 mg Acetaminophen Bilayer Tablets--Single Dose
[0578] The following study evaluated the bioavailability,
pharmacokinetics, dose-proportionality, and safety of 1 or 2
tablets of a formulation comprising 15 mg OC/650 mg APAP (1 dose)
(see selected example from Chart No. 1) compared to 1 tablet of the
commercially-available immediate release tablet under fed
conditions. The ER layer contained 75% of the total amount of the
oxycodone in the tablet, 50% of the total amount of APAP in the
tablet, and 45% (w/w) POLYOX.RTM. 1105. The IR layer contained 25%
of the total amount of oxycodone in the tablet and 50% of the total
amount of APAP. This study was conducted in 42 male and female
healthy subjects.
[0579] PK parameters for oxycodone are presented in Table 22.
Plasma concentrations of OC for the 1 tablet dosing configuration
of 15/650 showed a median t.sub.lag of 0.25 hours, while there was
no lag time for plasma concentrations of OC for the 2 tablet dosing
configuration of 15/650 and the commercially-available immediate
release tablet under fed conditions. As illustrated in FIG. 9
demonstrating the plasma concentrations of oxycodone versus time of
treatment (i.e., Treatment A was one tablet of 15 mg oxycodone/650
mg acetaminophen administered orally under fed conditions;
Treatment B was two tablets of 15 mg oxycodone/650 mg acetaminophen
administered orally one at a time under fed conditions; and
Treatment C was one tablet of the commercially-available immediate
release tablet (7.5 mg oxycodone/325 mg acetaminophen) administered
orally every 6 hours for 2 doses under fed conditions). Plasma
concentrations of OC rose rapidly after administration of 15/650
formulation in a similar fashion to commercially-available
immediate release tablet. Peak plasma levels of OC for the 15/650
tablets, however, were biphasic. Peak levels were observed at about
2-3 hours and about 6 hours for the 1 or 2 tablet dosing
configuration of the 15/650 formulation. In contrast, the peak
plasma level of OC for the commercially-available immediate release
tablet was about 7-8 hours after the initial dose of the
commercially-available immediate release tablet (.about.1-2 hr
after the second dose). Mean plasma concentrations of OC from
15/650 formulations were detectable through 48 hours following all
treatments and t.sub.112 was about 4 hours across all
treatments.
TABLE-US-00027 TABLE 22 Pharmacokinetic Parameter Estimates (Mean
.+-. SD) of Oxycodone Following Administration of 15 mg
Oxycodone/650 mg APAP versus Commercially-available immediate
release tablet C.sub.max AUC.sub.0-t AUC.sub.0-inf T.sub.max.sup.a
T.sub.lag.sup.a t.sub.1/2 Dosage (ng/mL) (nghr/mL) (nghr/mL) (hr)
(hr) (hr) One tablet 17.68 199.60 201.6 3.00 0.25 4.18 (N = 25)
(4.42) (59.52) (59.27) (1.00 - (0.00 - (0.77) Treatment A 12.45)
0.75) Two tablets 29.18 414.73 417.41.sup.b 5.00 0.00 4.11b (N =
25) (6.53) (109.87) (112.17) (1.00 - (0.00 - (0.67) Treatment B
12.00) 0.50) Commercially- 20.34 199.63 201.76 7.00 0.00 4.08
available (4.81) (60.53) (60.24) (0.50 - (0.00 - (0.64) immediate
9.00) 1.00) release tablet (7.5 mg OC/325 mg APAP (N = 25)
Treatment C .sup.aT.sub.max and t.sub.lag median (minimum -
maximum) .sup.bN = 24
[0580] PK parameters for APAP are presented in Table 23. Plasma
concentrations of APAP for the 1 tablet dosing configuration of
15/650 showed a median t.sub.lag of 0.25 hour, while there was no
lag in the appearance of APAP in plasma for the 2 tablet dosing
configuration of 15/650 and the commercially-available immediate
release tablet. Plasma concentrations of APAP rose rapidly after
administration of the 15/650 formulations, similar to that observed
with RDL. (See FIG. 10). Peak plasma levels of APAP following
administration of the 1 tablet and 2 tablet dosing configurations
of 15/650 were observed at approximately 2 hours (with a shoulder
peak at 5-6 hours) after dosing compared with 1 hour after the
second dose of the commercially-available immediate release tablet.
Mean plasma concentrations of APAP were detectable through 36 hours
following all treatments and the mean t.sub.1/2 was approximately 6
to 8 hours across treatment groups.
TABLE-US-00028 TABLE 23 Pharmacokinetic Parameter Estimates (Mean
.+-. SD) of APAP Following Administration of 15 mg Oxycodone/650 mg
APAP versus Commercially-available immediate release tablet
C.sub.max AUC.sub.0-t AUC.sub.0-inf T.sub.max.sup.a T.sub.lag.sup.a
t.sub.1/2 Dosage (ng/mL) (ng hr/mL) (ng hr/mL) (hr) (hr) (hr) One
tablet 3822 30239 32194.sup.c 2.00 0.25 6.17.sup.c (N = 25) (874)
(5673) (6437) (0.50 - (0.00 - 1.00) (2.22) 4.00) Two tablets 6941
64783 67600.sup.d 2.00 0.00 7.67.sup.d (N = 25) (1989) (15017)
(14655) (0.50 - (0.00 - 0.50) (4.06) 5.00) Commercially- 3629 30137
30802.sup.c 6.50 0.00 5.89.sup.c available immediate (841) (6426)
(6697) (0.50 - (0.00 - 1.00) (2.63) release tablet 9.00) (7.5 mg
OC/325 mg APAP (N = 25) .sup.aT.sub.max and t.sub.lag median
(minimum - maximum) .sup.cN = 21 .sup.dN = 23
Example 5
Clinical Pharmacokinetic Analysis of Controlled-Release 15 mg
Oxycodone/650 mg Acetaminophen Bilayer Tablets--Multiple Doses
[0581] The following study evaluated the steady state
bioavailability, pharmacokinetics, and safety of a 15 mg OC/650 mg
APAP composition administered (see selected example from Chart No.
2) orally as 1 tablet (Treatment A) or 2 tablets (Treatment B)
every 12 hours (9 doses) compared to 2 tablets of the
commercially-available immediate release tablet (2.times.7.5 mg
OC/325 mg APAP) (Treatment C) dosed every 6 hours for 4.5 days (18
doses) under fed conditions with 48 male and female subjects in
equal distribution.
[0582] The pharmacokinetic (PK) parameters of OC are presented in
Table 24. The PK behavior of OC on Study Day 1 was similar to that
observed in the single dose study (see Table 22). There was a
slight lag (median tlag 0.25 hr) in the appearance of OC following
the 1 tablet dose of 15 mg OC/650 mg APAP. No lag was observed
following dosing with 2 tablets of 15 mg OC/650 mg APAP or the
commercially-available immediate release tablet. Peak plasma levels
were observed at 4 and 6 hours after administration of 1 and 2
tablets of the 15/650 formulation, respectively, and at 1.5 hours
after the second dose of the commercially-available immediate
release tablet. (See FIG. 11). Minimum (trough) plasma
concentrations (C.sub.min) of OC achieved steady-state levels by
Day 2 for 15/650 formulations and by Day 3 for the
commercially-available immediate release tablet.
TABLE-US-00029 TABLE 24 Oxycodone Pharmacokinetic Parameters
C.sub.max AUC.sub.0-t T.sub.max.sup.a T.sub.lag.sup.a t.sub.1/2
Dosage (ng/mL) (ng hr/mL) (hr) (hr) (hr) A: One tablet 18.79
149.68.sup.c 4.00 0.25 Day 1 Day 1 (5.00) (37.92) (2.00-8.00)
(0.00-0.50) (N = 20) B: Two tablets 33.57 280.45.sup.c 5.93 0.00
Day 1 Day 1 (8.41) (62.61) (1.00-11.92) (0.00-0.25) (N = 20) C:
36.02 278.60.sup.c 7.50 0.00 Day 1 Commercially-available (10.52)
(67.17) (0.75-11.92) (0.00-0.33) immediate release tablet (7.5 mg
OC/325 mg APAP Day 1 (N = 20) A: One tablet 27.26 223.10.sup.c 3.00
Day 5 6.06.sup.d Day 5 (6.33) (59.45) (1.00-5.92) (1.91) (N = 20)
B: Two tablets 50.70 433.37.sup.c 3.00 Day 5 6.35 Day 5 (10.95)
(93.21) (2.00-7.00) (1.89) (N = 20) C: 52.41 435.70.sup.c 2.00 Day
5 5.93.sup.d Commercially-available (12.40) (98.68) (0.50-8.02)
(1.68) immediate release tablet (7.5 mg OC/325 mg APAP Day 5 (N =
20) .sup.aT.sub.max and t.sub.lag median (minimum-maximum)
.sup.cDay 1 - AUC.sub.0-12 h; Day 5 - AUC.sub.0-12 h ss .sup.dN =
19
[0583] On Day 5 of the study, the maximum plasma OC concentration
at steady-state (C.sub.max.sup.ss) was 27.3 ng/mL following 4.5
days of dosing with 1 tablet of 15 mg OC/650 mg APAP administered
every 12 hours. C.sub.max.sup.ss following 2 tablets of 15 mg
OC/650 mg APAP administered every 12 hours or the
commercially-available immediate release tablet administered Q6
hours for 4.5 days were 50.7 ng/mL and 52.4 ng/mL, respectively.
Median T.sub.max.sup.ss was observed at 3 hours following 1 tablet
or 2 tablets of 15/650 and at 2 hours following the first daily
dose of the commercially-available immediate release tablet.
[0584] PK parameters for APAP are presented in Table 25.
Acetaminophen was rapidly absorbed following a single dose of 1 or
2 tablets of 15/650 and in a similar fashion to the
commercially-available immediate release tablet (see FIG. 12).
There was no lag in plasma concentrations following any of the
three dosing regimens. Peak APAP plasma concentrations were
observed at 1 hour after administration of 1 or 2 tablets of 15/650
and at 0.9 hours after the first dose of the commercially-available
immediate release tablet on Day 1. After a single administration of
15/650, C.sub.max for APAP was proportional with respect to the
amount of APAP in 1 or 2 tablets of 15/650 (i.e., 1 tablet--3942
ng/mL; 2 tablets--7536 ng/mL). Minimum (trough) concentrations
(C.sub.min) of APAP achieved steady-state levels by Day 2 for 1
tablet of 15/650, by Day 4 for 2 tablets of 15/650 and by the
second dose on Day 1 for the commercially-available immediate
release tablet.
TABLE-US-00030 TABLE 25 Acetaminophen Pharmacokinetic Parameters
C.sub.max AUC.sub.0-t T.sub.max.sup.a T.sub.lag.sup.a t.sub.1/2
Dosage (ng/mL) (ng hr/mL) (hr) (hr) (hr) A: One tablet 3942
22928.sup.g 1.00 0.00 Day 1 Day 1 (1168) (7331) (0.50-5.93)
(0.00-0.28) (N = 20) B: Two tablets 7536 .sup. 44254.sup.g 1.00
0.00 Day 1 Day 1 (2205) (13885) (0.28-4.00) (0.00-0.25) (N = 20) C:
6757 .sup. 43634.sup.g 0.90 0.00 Day 1 Commercially-available
(1949) (12357) (0.32-11.92) (0.00-0.25) immediate release tablet
(7.5 mg OC/325 mg APAP Day 1 (N = 20) A: One tablet 4635 .sup.
26968.sup.g 1.00 Day 5 7.06 Day 5 (1330) (9134) (0.50-3.00) (2.24)
(N = 20) B: Two tablets 8206 .sup. 50221.sup.g 1.00 Day 5 7.46 Day
5 (2666) (18415) (0.30-4.00) (1.85) (N = 20) C: 7433 .sup.
50678.sup.g 1.50 Day 5 6.79.sup.h Commercially-available (1979)
(15565) (0.25-8.02) (2.47) immediate release tablet (7.5 mg OC/325
mg APAP Day 5 (N = 20) .sup.aT.sub.max and t.sub.lag median
(minimum-maximum) .sup.gDay 1 - AUC.sub.0-12 h; Day 5 -
AUC.sub.0-12 h.sup.ss .sup.hN = 17
[0585] On Day 5 of the study, median T.sub.max.sup.ss for APAP was
observed at 1 hour following 1 or 2 tablets of 15/650 and at 1.5
hours following the first daily dose of the commercially-available
immediate release tablet on Day 5. Maximum plasma APAP
concentration at steady-state (C.sub.max.sup.ss) was 4635 ng/mL
following 4.5 days of dosing with 1 tablet of 15/650 every 12 hours
(Table 25). C.sub.max.sup.ss following 2 tablets of 15/650
administered every 12 hours and for the commercially-available
immediate release tablet administered Q6 hours for 4.5 days were
8206 and 7433 ng/mL, respectively.
Example 6
Clinical Pharmacokinetic Analysis of Controlled-Release 15 mg
Oxycodone/650 mg Acetaminophen Bilayer Tablets Under Fed and Fasted
Conditions
[0586] Two open-label, randomized, two-period crossover studies
were conducted to evaluate the effect of food on the
pharmacokinetics, bioavailability and safety of the 15 mg
oxycodone/650 mg APAP composition (see selected example from Chart
No. 2) using a 1 tablet or 2 tablet dosing configuration in normal,
healthy subjects. Studies were conducted in 48 subjects under fed
(FDA high fat breakfast) or fasted conditions.
[0587] Tables 26 and 27 present the pharmacokinetic data for
oxycodone (OC) and APAP, respectively. FIGS. 13 and 14 present the
plasma concentration of OC following administration of one tablet
and two tablets, respectively, under fed (Treatment A) or fasted
(Treatment B) conditions. FIGS. 15 and 16 present the plasma
concentration of APAP following administration of one tablet and
two tablets, respectively, under fed (Treatment A) or fasted
(Treatment B) conditions.
TABLE-US-00031 TABLE 26 Oxycodone Pharmacokinetics (15/650)
AUC.sub.0-t AUC.sub.0-inf State C.sub.max (ng hr/ (ng hr/
T.sub.max.sup.a t.sub.lag.sup.a t.sub.1/2 Dose (N) (ng/mL) mL) mL)
(hr) (hr) (hr) One fed 19.03 (4.20) 219.23 221.06 5.00 0.25 3.94
tablet (28) (55.99) (55.88) (1.00 - (0.00 - (0.69) 12.00) 0.50) Two
fed 30.58 (6.57) 414.01 415.88 5.00 0.25 4.42 tablets (17) (104.76)
(104.86) (0.75 - (0.00 - (0.97) 12.00) 0.27) One fasted 18.31
(4.67) 196.51 198.33 3.50 0.00 4.25 tablet (28) (53.04) (52.82)
(0.50 - (0.00 - (0.59) 10.00) 0.25) Two fasted 33.69 (7.45) 390.33
392.15 5.00 0.00 4.80 tablets (17) (145.27) (145.81) (2.00 - (0.00
- (1.07) 5.20) 0.25) .sup.aT.sub.max and t.sub.lag median (minimum
- maximum)
[0588] Plasma concentrations (Table 26; FIGS. 13 and 14) of OC rose
rapidly with the median T.sub.max observed at about 4 to 5 hr under
both fed and fasted conditions for both the 1- and 2-tablet dose
configurations. OC plasma levels were biphasic--with a first peak
at about 3 hours and a second peak at about 5 hours. The C.sub.max
values (at 5 hours) for OC under fed (1 and 2 tablets, 19.0 and
30.6 ng/mL) conditions were equivalent to those observed under
fasted (1 and 2 tablets, 18.3 and 33.7 ng/mL) conditions for both
the 1 tablet and 2 tablet dosing configurations.
TABLE-US-00032 TABLE 27 Acetaminophen Pharmacokinetics (15/650)
State C.sub.max AUC.sub.0-t AUC.sub.0-inf T.sub.max.sup.a
t.sub.lag.sup.a t.sub.1/2 Dose (N) (ng/mL) (nghr/mL) (nghr/mL) (hr)
(hr) (hr) One tablet fed 4374 31480 32552 1.00 0.00 4.65 (28)
(1286) (9316) (9489) (0.50, (0.00 - 0.50) (1.26) 5.00) Two tablets
fed 6341 62904 68839.sup.b 2.00 0.00 7.02.sup.b (17) (1698) (19294)
(19826) (0.75 - (0.00 - 0.25) (1.77) 6.00) One tablet fasted 5511
31876 33860 0.75 0.00 5.19.sup.e (28) (2095) (103339) (10731)
(0.25, (0.00 - 0.25) (1.50) 5.00) Two tablets fasted 10428 61164
65281 0.75 0.00 5.6 (17) (3529) (16652) (15711) (0.25 - (0.00 -
0.00) (1.49) (5.00) .sup.aT.sub.max and t.sub.lag median (minimum -
maximum) .sup.b N = 12 .sup.e N = 27 .sup.f N = 13
[0589] Plasma concentrations (Table 27; FIGS. 15 and 16) of APAP
rose rapidly following 1 tablet dosed under fed and fasted
conditions with similar T.sub.max values (1.0 hour and 0.8 hour).
T.sub.max was observed sooner following 2 tablets given under
fasted conditions (0.8 hour) than under fed conditions (2 hours).
Plasma concentrations of APAP were lower under fed conditions than
under fasted conditions with fed C.sub.max values of 4374 ng/mL (1
tablet) and 6341 ng/mL (2 tablets) and fasted C.sub.max values of
5511 ng/mL (1 tablet) and 10,428 ng/mL (2 tablets). Nevertheless,
the peak concentrations demonstrate that there was only a slight,
minimal food effect on the absorption of APAP, which is consistent
with that observed for other oxycodone and acetaminophen products.
Thus, there is no meaningful food effect seen with this
composition, and as such, the composition can to be administered
without regard to food.
Example 7
Abuse Potential of Controlled-Release Formulations
[0590] It has long been theorized that the desirability of a drug
of abuse is related to the speed with which it reaches maximum
concentration in the plasma of the user. Basic science and clinical
observation suggest that a shortened time to maximum plasma
concentration (t.sub.max) and a heightened maximum plasma
concentration (C.sub.max) would increase the euphoric effects
conferred by a drug. The abuse quotient (AQ) is a relatively new
concept that attempts to predict the abuse potential of drugs. The
AQ refers to the two PK parameters expressed as a ratio:
AQ=C.sub.max/t.sub.max. The abuse potential of a drug increases as
the value of the AQ increases, either by heightening C.sub.max or
shortening t.sub.max.
[0591] Table 28 presents the AQs for various extended release
formulations disclosed herein (see, e.g., selected examples from
Chart Nos. 1 and 2) and several commercially available
formulations.
TABLE-US-00033 TABLE 28 Abuse Quotient Formulation C.sub.max
(ng/mL) t.sub.max (hr) AQ 15/500 - Fast 18.8 4.95 3.80 15/500 -
Medium 18.27 5.31 3.44 15/500 - Slow 17.4 5.66 3.07 15/650 - 1
tablet 17.68 3.90 4.53 15/650 - 2 tablets 14.59* 5.03 2.90 7.5/325
- 1 tablet 16.82 3.71 4.53 7.5/325 - 2 tablets 16.39 3.17 5.17
Percocet 22.43 2.16 10.38 Oxycontin 17.35 3.54 4.90 OxyER 19.61
4.11 4.77 *dose normalized to 15 mg
Example 8
Ethanol Release Testing at a 150 rpm Paddle Speed
[0592] To assess the potential for dose dumping, the in vitro
dissolution of oxycodone and APAP from 7.5 mg OC/325 mg APAP
tablets was tested in 0.1 N HCl containing 0%, 5%, 20%, or 40% v/v
ethanol. The ER layer of the 7.5/325 tablets contained 5.625 mg of
OC, 162.5 mg of APAP, and 45% (w/w) POLYOX.RTM. 1105, and the IR
layer contained 1.875 mg of OC and 162.5 mg of APAP. (See selected
example from Chart No. 1.) For each profile, twelve tablets were
weighed, placed in a sinker, and dropped into an equilibrated USP
Type II apparatus (paddles) that contained 900 mL of (helium
sparged) 0.1 N HCl (containing either 0%, 5%, 20%, or 40% ethanol)
heated to .about.37.degree. C. The mixture was stirred at
.about.150 rpm and the temperature was maintained at
.about.37.degree. C. for 120 minutes. The bath vessel was covered
with a low evaporation vessel cover. Samples were removed at 15,
30, 45, 60, 75, 90, 105, and 120 minutes. Each sample was filtered
through a 0.45 .mu.m filter and analyzed by HPLC using standard
procedures.
[0593] Tables 29, 30, 31, and 32 present the percent release of OC
and APAP in the presence of 0%, 5%, 20%, and 40% ethanol,
respectively. FIG. 17 presents dissolution profiles for OC and FIG.
18 presents dissolution profiles for APAP in the presence of 0%,
5%, 20%, and 40% ethanol. These data reveal that, for both OC and
APAP, the dissolution in 5%, 20%, or 40% ethanol was either
comparable or slower than the dissolution in 0% ethanol, indicating
no dose dumping for this formulation.
TABLE-US-00034 TABLE 29 Percent Release in 0% Ethanol OC APAP Time
(Min) Mean RSD Minimum Maximum Mean RSD Minimum Maximum 15 32.0 2.7
31.1 33.4 52.9 2.7 50.6 56.0 30 37.6 2.4 36.5 39.2 55.6 2.5 53.5
58.6 45 42.3 2.6 40.9 44.4 58.1 2.5 56.0 61.1 60 46.5 2.5 45.0 48.7
60.5 2.4 58.4 63.5 75 50.4 2.5 48.7 52.5 62.9 2.4 60.8 65.9 90 54.1
2.4 52.1 56.2 65.0 2.3 62.9 68.0 105 57.7 2.1 55.6 59.8 67.1 2.3
65.0 70.1 120 61.1 2.2 58.9 63.5 69.1 2.2 66.9 72.1
TABLE-US-00035 TABLE 30 Percent Release in 5% Ethanol OC APAP Time
(Min) Mean RSD Minimum Maximum Mean RSD Minimum Maximum 15 31.2 2.4
30.2 32.4 52.1 1.5 50.5 53.5 30 36.9 3.2 35.1 39.0 54.9 1.6 53.4
56.4 45 41.5 3.3 39.1 44.0 57.2 1.5 55.7 58.7 60 45.5 3.5 43.4 48.2
59.4 1.5 57.9 60.9 75 49.4 2.6 47.9 52.5 61.5 1.5 60.0 63.0 90 52.9
3.5 50.7 56.1 63.4 1.5 61.9 65.0 105 56.2 1.8 54.0 57.8 65.4 1.5
63.8 66.9 120 59.3 2.8 56.7 61.7 67.2 1.5 65.6 68.7
TABLE-US-00036 TABLE 31 Percent Release in 20% Ethanol OC APAP Time
(Min) Mean RSD Minimum Maximum Mean RSD Minimum Maximum 15 28.5 4.1
26.5 30.3 51.3 2.9 48.2 53.1 30 33.6 3.3 32.3 35.7 54.1 2.3 51.3
55.7 45 38.3 2.8 35.7 39.9 56.3 2.2 53.7 58.0 60 41.8 3.6 38.1 44.1
58.3 2.1 55.6 59.9 75 45.6 3.0 43.4 48.8 60.2 2.0 57.7 61.8 90 48.7
3.3 46.1 52.0 62.0 2.0 59.4 63.6 105 51.4 3.0 49.1 53.7 63.7 1.9
61.1 65.2 120 54.3 2.7 51.3 56.7 65.4 1.9 62.9 66.8
TABLE-US-00037 TABLE 32 Percent Release in 40% Ethanol Time OC APAP
(Min) Mean RSD Minimum Maximum Mean RSD Minimum Maximum 15 10.3
16.3 7.8 13.7 20.7 16.3 15.8 25.9 30 20.7 8.6 16.5 23.0 37.1 7.7
31.4 41.4 45 28.6 10.4 24.4 33.4 44.4 2.6 42.2 45.8 60 31.3 5.9
29.2 35.0 47.0 1.4 45.9 48.0 75 34.5 6.5 30.3 38.1 49.0 1.4 47.7
49.8 90 36.8 7.0 33.9 41.2 50.5 1.5 49.2 51.6 105 38.5 6.8 35.3
44.0 51.9 1.7 50.4 53.1 120 40.7 4.5 38.0 43.5 53.2 1.4 51.5
54.1
Example 9
Clinical Pharmacokinetic Analysis of an Extended Release
Formulation of Oxycodone/Acetaminophen Administered Under Fed and
Fasted Conditions
[0594] An open-label, randomized, three-period crossover study was
conducted to evaluate the pharmacokinetics (PK), bioavailability,
and safety of two tablets of a multi-layer extended-release
formulation (each tablet comprising 7.5 mg oxycodone
hydrochloride/325 mg acetaminophen), administered as a single dose
in normal, healthy subjects under fed (high-fat or low-fat meal)
and fasted conditions (i.e., 10 hr fast).
[0595] This single center, open-label, randomized, 3-period,
6-sequence crossover study in normal, healthy subjects was designed
to evaluate the effect of a high-fat and low-fat meal on the PK,
bioavailability, and safety of a multilayer ER tablet formulation
of 7.5 mg OC/325 mg APAP (see selected example from Chart No. 1).
The formulation was orally administered as 2 tablets (15 mg OC/650
mg APAP total dose) under 2 types of fed (high-fat and low-fat) and
fasted conditions.
[0596] The study population included 48 normal, healthy male and
female subjects aged 18 to 55 years. Eligibility criteria included:
body mass index (BMI) between .gtoreq.19 and .ltoreq.30 kg/m.sup.2,
with a minimum weight of 130 lb; if female, non-pregnant and
non-lactating; commitment to the use of 2 methods of birth control
in subjects of child-bearing potential; ability to consume the
entire standardized FDA high-fat meal or a low-fat meal in 30
minutes prior to dosing. Exclusion criteria included: history of
drug abuse or treatment for abuse; positive urine test results for
drugs of abuse, alcohol, and/or nicotine; history of smoking or use
of nicotine-containing products within 6 months prior to study
onset; history of drug allergy, hypersensitivity, or intolerance,
including to oxycodone, APAP, or any opioid analgesic; history of
any condition that may interfere with the absorption, distribution,
metabolism, or excretion of study medication; or previous gastric
bypass or gastric band surgery. Each crossover period required
confinement of approximately 60 hours, and each period was
separated by a minimum 7-day washout period. For subjects with
ongoing adverse events, a follow-up visit occurred .gtoreq.7 days
after the conclusion of the study; if a serious adverse event was
ongoing at follow-up, the investigator continued to follow the
subject for up to 28 days.
[0597] Following a 10 hour overnight fast, subjects randomized to
Treatment A consumed an entire standardized FDA high-fat breakfast
(approximately 1,000.+-.100 calories and approximately 50% from
fat); those receiving Treatment B consumed an entire low-fat
breakfast (approximately 800.+-.80 calories and approximately 25%
to 30% from fat). Breakfasts were consumed within 30 minutes prior
to Hour 0 study drug administration. Subjects who could not consume
the entire breakfast in the allotted time were dropped from the
study. Subjects randomized to Treatment C were administered study
drug under fasted conditions following an overnight fast of at
least 10 hours. No food was allowed for the first 4 hours postdose.
Blood samples were collected pre-dose (up to 60 minutes prior to
dose), and at 15 min, 30 min, 45 min and 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 12, 16, 18, 20, 24, 36 and 48 hours post-dose, and the
resulting plasma samples were analyzed for OC and APAP using a
validated liquid chromatography-tandem mass spectrometry assay with
a linear range of 0.100 to 100 ng/mL for OC and 100 to 50,000 ng/mL
for APAP. Pharmacokinetic parameters, as detailed above in Example
2, were determined.
[0598] PK parameters of oxycodone and APAP were estimated using
plasma concentration versus time data by standard non-compartmental
methods. The Wilcoxon signed-rank test was utilized to compare
untransformed time to maximum observed plasma concentration
(T.sub.max) and time prior to the first measurable concentration
(t.sub.lag); P.ltoreq.0.05 was considered a significant difference
between treatments. Analysis of variance was performed to compare
data from Treatments A, B, and C using the natural log transformed
PK parameters area under the plasma drug concentration versus time
curve from time zero to the last quantifiable data point
(AUC.sub.0-t), AUC from time zero to infinity (AUC.sub.0-inf), and
maximum observed plasma concentration (C.sub.max). A 90% confidence
interval (CI) of the geometric least-squares (LS) means ratio
contained within 80% to 125% concluded no difference between
treatments.
[0599] A total of 48 subjects enrolled and received study
medication (safety population). Of these subjects, 31 (65%)
completed all 3 periods of the study (completers, PK population).
Of the 17 subjects (35%) who discontinued early from the study, 14
withdrew due to vomiting (withdrawn per protocol) and 3 met other
withdrawal criteria. Baseline demographics were comparable between
the enrolled subjects and completers, except that there was a
higher percentage of male subjects among the completers (68% vs
52%).
[0600] Tables 33 and 34 presents PK parameters for OC under the
three treatment conditions, and FIG. 19 presents plasma OC
concentration-time profiles for the treatments. Mean plasma
concentration profiles of OC revealed that OC was rapidly absorbed
under both fed (high and low fat meal) and fasted conditions. There
was a slight lag (median 0.25 hours) when the formulation was
administered after a meal (high and low fat). The median of the
time of observed maximum plasma concentrations (T.sub.max) were 4
hours and 3 hours after administration under low fat and fasted
conditions, respectively. Median T.sub.max for OC under high fat
conditions was statistically significantly delayed, as compared to
fasted conditions (5 hr vs. 3 hr; P<0.05). Average maximum
plasma OC concentrations (C.sub.max) were 19.94 ng/mL after a low
fat breakfast, 17.90 ng/mL after a high fat breakfast, and 15.91
ng/mL under fasted conditions.
TABLE-US-00038 TABLE 33 Pharmacokinetic Parameters for Oxycodone
Following Administration of ER OC/APAP (2 Tablets of 7.5/325) Under
Fed and Fasted Conditions (n = 31) Treatment A Treatment B
Treatment C High Fat Low Fat Fasted Mean (SD) Mean (SD) Mean (SD)
Parameter (N = 31) (N = 31) (N = 31) AUC.sub.0-t (ng h/mL) 219.41
(54.07) 219.49 (57.29) 190.70 (50.03) AUC.sub.0-inf (ng h/mL)
221.00 (54.14) 221.38 (56.95) 192.63 (49.69) C.sub.max (ng/mL)
17.90 (4.25) 19.94 (4.66) 15.91 (3.43) T.sub.max (h).sup.a 5.00
(1.00-12.00) 4.00 (1.00-5.00) 3.00 (0.75-8.00) K.sub.el (1/h)
0.1682 (0.0298) 0.1693 (0.0321) 0.1502 (0.0269) t.sub.lag (h).sup.a
0.25 (0.00-1.00) 0.25 (0.00-0.75) 0.00 (0.00-0.25) t.sub.1/2 (h)
4.26 (0.83) 4.26 (0.91) 4.76 (0.87) .sup.aMedian
(minimum-maximum).
[0601] A comparison of C.sub.max showed that OC concentrations were
12% and 25% higher when the formulation was given under high fat
(Treatment A) and low fat (Treatment B) conditions, compared to
fasted conditions (Treatment C; see Table 33). The C.sub.max for
Treatment A was bioequivalent to both Treatments B (84%-96%) and C
(105%-120%) as the 90% CIs for the geometric ratios were contained
within 80% to 125% (see Table 34). The C.sub.max observed for
Treatment B was not bioequivalent to Treatment C (117%-134%). AUCs
were approximately 15% higher when the formulation was administered
under fed conditions (high and low fat), as compared to fasted
conditions (Table 33). AUC for both Treatments A and B (high fat
and low fat) were bioequivalent to Treatment C (fasted; 111%-121%
and 111%-120% for AUC0-t and 111%-120% and 110%-120% for AUC0-inf)
(Table 34). The apparent plasma terminal elimination half-life
(t1/2) for OC was similar when the formulation was administered
under fed (4 hours) and fasted conditions (5 hours).
TABLE-US-00039 TABLE 34 Oxycodone Geometric LS Mean Ratios (AUC and
C.sub.max) and 90% Cls for the Comparison of ER OC/APAP Under Fed
and Fasted Conditions (n = 31) Treatment A/C Treatment B/C
Treatment A/B Fed (High Fed (Low Fed (High Fat)/ Parameter
Fat)/Fasted Fat)/Fasted Fed (Low Fat) AUC.sub.0-inf 115.41 115.09
100.28 (ng h/mL).sup.a (110.63, 120.41) (110.38, 120.01) (96.18,
104.55) AUC.sub.0-t 115.85 115.30 100.47 (ng h/mL).sup.a (111.00,
120.90) (110.54, 120.27) (96.34, 104.79) C.sub.max (ng/mL).sup.a
112.11 125.16 89.57 (104.61, 120.16) (116.88, 134.03) (83.67,
95.90) .sup.aN = 31.
[0602] PK parameters for APAP are presented in Tables 35 and 36 and
the plasma APAP concentration-time profiles are presented in FIG.
20. APAP was rapidly absorbed following administration under fed
(high and low fat meals) and fasted conditions. There was a slight
lag when the formulation was administered after a low fat breakfast
(median lag time [t.sub.lag] 0.25 hours). There was no lag in the
absorption of APAP when administered following a high fat breakfast
or after fasting. The time to C.sub.max was significantly
(P<0.05) longer when administered after a meal (high and low
fat; median T.sub.max=2 hours) than when administered under fasted
conditions (median T.sub.max=0.5 hour). Average C.sub.max values
for APAP were lower after a high (3,775 ng/mL) and low fat (3,863
ng/mL) meal than when administered under fasted conditions (5,175
ng/mL). Geometric mean ratios for C.sub.max following Treatments A
and B were 24% to 23% lower than for Treatment C (Table 36). The
90% CIs for C.sub.max following Treatment A (70%-82%) and Treatment
B (72%-83%) with reference to fasted state were outside the
bioequivalent range of 80%-125%. The AUCs for APAP were almost
identical when the formulation was administered under high fat, low
fat, or fasting conditions. (Comparison of geometric mean ratios of
AUC.sub.0-t and AUC.sub.0 inf for Treatments A (90% CI 97%-103% and
96%-102%) and B (90% CI 96%-101% and 94% to 100%) with those for
Treatment C showed that treatments were bioequivalent. The
t.sub.1/2 for APAP after the formulation was administered after a
high or low fat meal (5 hours) was slightly shorter than when
administered under fasted conditions (7 hours).
TABLE-US-00040 TABLE 35 Pharmacokinetic Parameters for APAP
Following Administration of ER OC/APAP (2 Tablets of 7.5/325) Under
Fed and Fasted Conditions (n = 31) Treatment A Treatment B
Treatment C Fed (High Fat) Fed (Low Fat) Fasted Mean (SD) Mean (SD)
Mean (SD) Parameter (N = 31) (N = 31) (N = 31) AUC.sub.0-t (ng
h/mL) 29617.96 (7765.99) 29346.82 (7869.75) 29763.19 (7592.89)
AUC.sub.0-inf (ng h/mL) 31457.06 (7973.16).sup.a 30550.48 (8051.47)
31807.70 (7923.30).sup.a C.sub.max (ng/mL) 3774.52 (949.84) 3862.90
(978.08) 5175.48 (1731.31) T.sub.max (h).sup.b 2.00 (0.50-5.00)
2.00 (0.50-5.00) 0.53 (0.23-5.00) K.sub.el (1/h) 0.1564
(0.0363).sup.a 0.1593 (0.0408) 0.1146 (0.0360).sup.a t.sub.lag
(h).sup.b 0.00 (0.00-1.00) 0.25 (0.00-0.50) 0.00 (0.00-0.25)
t.sub.1/2 (h) 4.66 (1.08).sup.a 4.71 (1.60) 6.63 (1.99).sup.a
.sup.aN = 29 .sup.bMedian (minimum-maximum).
TABLE-US-00041 TABLE 36 Acetaminophen Geometric LS Mean Ratios (AUC
and C.sub.max) and 90% Cls for the Comparison of ER OC/APAP Under
Fed and Fasted Conditions Treatment A/C Treatment B/C Treatment A/B
Fed (High Fed (Low Fed (High Fat)/ Parameter Fat)/Fasted
Fat)/Fasted Fed (Low Fat) AUC.sub.0-inf 98.60 96.56 102.12 (ng
h/mL).sup.a (95.75, 101.54) (93.80, 99.39) (99.20, 105.11)
AUC.sub.0-t 99.88 98.79 101.10 (ng h/mL).sup.b (97.31, 102.52)
(96.27, 101.37) (98.54, 103.74) C.sub.max (ng/mL).sup.b 76.00 77.18
98.48 (70.49, 81.94) (71.65, 83.13) (91.45, 106.05) .sup.aN = 27
.sup.bN = 31
[0603] Reports of adverse events were also collected and monitored
throughout the study. Table 36A presents a summary of the most
frequently occurring (>10% overall) treatment-emergent adverse
events. 33 participants (68.8%) reported .gtoreq.1 TEAE. The most
frequently reported TEAEs were nausea, vomiting, and dizziness, and
there were no notable differences between treatment groups. All
TEAEs were determined by the investigator to be either mild or
moderate in severity; all resolved after discontinuation of
treatment.
TABLE-US-00042 TABLE 36A Summary of Most Frequently Occurring
(>10% Overall) Treatment Emergent Adverse Events High-Fat Meal
Low-Fat Meal Fasted Overall TEAE, n (%) (n = 37) (n = 38) (n = 39)
(N = 48) Any TEAE 16 (43.2) 17 (44.7) 15 (38.5) 33 (68.8) Nausea 10
(27.0) 8 (21.1) 8 (20.5) 21 (43.8) Vomiting 5 (13.5) 5 (13.2) 5
(12.8) 15 (31.3) Dizziness 5 (13.5) 6 (15.8) 2 (5.1) 10 (20.8)
Somnolence 1 (2.7) 2 (5.3) 3 (7.7) 6 (12.5) Euphoric mood 2 (5.4) 1
(2.6) 4 (10.3) 6 (12.5) Pruritus 3 (8.1) 4 (10.5) 0 5 (10.4)
[0604] The results of this study demonstrate that total oxycodone
and APAP exposures (AUC) were not significantly affected by food.
Minimal changes in C.sub.max for oxycodone and APAP were noted in
the presence of food, but these changes were comparable to food
effects on peak exposure for other oxycodone and APAP products.
Food marginally delayed the T.sub.max of oxycodone and APAP. ER
OC/APAP was generally well tolerated. There was no indication that
safety or tolerability were affected by food. These findings
demonstrate that ER OC/APAP can be administered with or without
food.
Example 10
Clinical Pharmacokinetic Analysis of an Extended Release
Formulation of 7.5 mg Oxycodone/325 mg Acetaminophen--Single
Dose
[0605] A single-center, open-label, randomized, phase 1, 3-period
crossover study was performed to evaluate the single dose
pharmacokinetic (PK) parameters, bioavailability, and safety of an
extended-release formulation containing 7.5 mg OC/325 mg APAP (see
selected example from Chart No. 1) in healthy subjects under fasted
conditions. The PK and bioavailability of the extended-release
formulation administered as 1 or 2 tablets were compared to the
commercially-available immediate release tablet (immediate release
7.5 mg OC/325 mg APAP) administered as 1 or 2 tablets every 6 hours
for 2 doses.
[0606] This study was conducted in 48 male and female subjects,
with equal gender distribution. Normal healthy male or
non-lactating, non-pregnant female subjects aged 18 to 55 years
with body mass index of .gtoreq.9 to .ltoreq.30 kg/m.sup.2 and a
minimum weight of 130 lb were eligible for participation. Exclusion
criteria included smoking or use of nicotine-containing products in
the previous 6 months; history of drug or alcohol use or positive
urine test for drugs of abuse; use of prescription or
over-the-counter drugs within 14 days of study check-in; history of
drug allergy, hypersensitivity, or intolerance of opioid drug
products (including oxycodone) or APAP; history of any condition
that may interfere with the absorption, distribution, metabolism,
or excretion of study drug; or previous gastric bypass or gastric
band surgery. A total of 48 adults were enrolled; 33 completed 3
treatment periods (primary completers), and 27 completed all 4
treatment periods (secondary completers).
[0607] Completers of the first 3 periods of this study entered a
fourth treatment period that served as a second phase of the study.
The 4 treatment periods (A, B, C, and D) each utilized a unique
dosing scheme. Subjects were randomized to receive the following
treatments in a 3-way crossover design under fasted conditions:
[0608] Treatment A: 1-tablet dosing of ER OC/APAP (7.5 mg OC/325 mg
APAP) (see selected example from Chart No. 1) taken once [0609]
Treatment B: 2-tablet dosing of ER OC/APAP (total, 15 mg OC/650 mg
APAP) (see selected example from Chart No. 1) taken once [0610]
Treatment C: 1-tablet dosing of commercially-available IR OC/APAP
(7.5 mg OC/325 mg APAP) taken every 6 hours for 2 doses (total, 15
mg OC/650 mg APAP)
[0611] Subjects who completed periods 1, 2, and 3 returned for
period 4 and received Treatment D (2-tablet dosing of IR OC/APAP
every 6 hours for 2 doses [total, 30 mg OC/1300 mg APAP] under
fasted conditions). The study included a screening visit and 4
confinement periods of approximately 60 hours each, with a minimum
of 7 days between the start of each period, and a minimum 7-day
follow-up period.
[0612] Blood was collected predose and 15, 30, and 45 minutes and
1, 2, 3, 4, 5, 6, 6.5, 7, 8, 9, 10, 12, 16, 18, 20, 24, 36, and 48
hours after dosing. PK parameters (AUC.sub.0-t, AUC.sub.0-inf,
C.sub.max, T.sub.max, t.sub.lag, K.sub.el, and t.sub.1/2) for
oxycodone and APAP were calculated by noncompartmental methods.
Analysis of variance was performed to compare treatment conditions
A, B, and C using the dose-normalized (plasma concentration divided
by dose) natural log-transformed PK parameters (AUC.sub.0-inf,
AUC.sub.0-t, and C.sub.max), and linear mixed models analysis
compared the same PK parameters for treatments C and D. Dose
normalization was utilized to compare concentration across
different dosage strengths. A 90% confidence interval of the
geometric least-squares means ratio fully contained within 80% to
125% for AUC.sub.0-inf, AUC.sub.0-t, and C.sub.max indicated no
difference between treatments. Dose-normalized AUC and C.sub.max
for oxycodone and APAP were used for comparisons.
[0613] Pharmacokinetic parameter estimates for OC are presented in
Table 37A, and OC plasma concentration-time profiles are presented
in FIG. 21. There was no lag in absorption of OC for the 1 and 2
tablet dosing configurations of the extended release formulation
and the commercially-available immediate release tablet under
fasted conditions. Plasma concentrations of OC rose rapidly after
administration of the extended release formulation in a similar
fashion to the commercially-available immediate release tablet, and
peak plasma levels of OC were observed (T.sub.max) at 4 and 3 hours
for the 1 or 2 tablet dosing configuration of the extended release
formulation compared with 7 hours after the initial dose of 1
tablet of the commercially-available immediate release tablet (1
hour after the second dose) and 0.75 hours after the initial dose
of 2 tablets of the commercially-available immediate release
tablet. Mean plasma concentrations of OC from the extended release
formulation were detectable through 36 hours in most subjects
following all treatments and t.sub.1/2 was about 4 to 5 hours
across all treatments. The extent of exposure (AUC.sub.0-t and
AUC.sub.0-inf) for the 2 tablet dosing configuration of the
extended release formulation increased proportionally with dose
compared with the 1-tablet dosing configuration of the extended
release formulation. Dose-normalized oxycodone AUC.sub.0-t and
AUC.sub.0-inf were comparable across treatments A, B, and C,
indicating similar bioavailability of oxycodone for ER OC/APAP (1
or 2 tablets once) and IR OC/APAP (1 tablet twice). The
dose-normalized oxycodone C.sub.max was comparable for the 1- and
2-tablet doses of ER OC/APAP, indicating dose proportionality of
oxycodone between 1 and 2 tablets of ER OC/APAP.
TABLE-US-00043 TABLE 37A Oxycodone Pharmacokinetic Estimates
(7.5/325) Treatment C Treatment D Treatment A Treatment B IR
OC/APAP IR OC/APAP ER OC/APAP ER OC/APAP (1 tablet (2 tablets (1
tablet; (2 tablets; twice; twice; 7.5/325 mg) 15/650 mg) 15/650
mg.sup.c) 30/1300 mg.sup.c) Parameter (n = 33) (n = 33) (n = 33) (n
= 27.sup.d) AUC.sub.0-t 87.43 (24.59) 185.98 (47.64) 191.15 (53.43)
401.23 (110.56) (ng h/mL) AUC.sub.0-inf 89.85 (24.73).sup.b 187.71
(47.58) 193.10 (53.22) 403.04 (110.45) (ng h/mL) C.sub.max (ng/mL)
8.41 (2.06) 16.39 (4.31) 20.82 (5.98) 41.24 (12.12) T.sub.max
(h).sup.a 4.00 (0.75-5.92) 3.00 (0.75-6.50) 7.38 (0.50-10.00) 0.75
(0.50-12.00) t.sub.lag (h).sup.a 0.00 (0.00-0.50) 0.00 (0.00-0.52)
0.00 (0.00-0.25) 0.00 (0.00-0.25) t.sub.1/2 (h) 4.50 (0.78).sup.b
4.87 (0.93) 4.08 (0.89) 4.34 (1.02) K.sub.el (h.sup.-1) 0.1590
(0.0307).sup.b 0.1473 (0.0274) 0.1770 (0.0352) 0.1688 (0.0415)
.sup.aMedian (minimum-maximum). .sup.bN = 32
[0614] No dose-dumping was observed in any subject receiving the ER
formulation. The interindividual variability (CV %) for C.sub.max
of OC after administration of 1 or 2 tablets of the ER formulation
was comparable to 1 tablet of the commercially-available immediate
release tablet and less than 29% for all 3 treatments. Similarly
the interindividual variability (CV %) for AUC of OC was 28% or
less for 1 and 2 tablets of the ER formulation and 1 tablet of the
commercially-available immediate release tablet.
[0615] Table 37B presents APAP PK parameter estimates and FIG. 22
presents APAP plasma concentration-time profiles. The appearance of
plasma concentrations of APAP for all dose configurations of the
extended release formulation and the commercially-available
immediate release tablet showed no lag. Plasma concentrations of
APAP rose rapidly after administration of the extended release
formulation, similar to that observed with the
commercially-available immediate release tablet. APAP C.sub.max was
comparable for 2 tablets of ER OC/APAP and 1 tablet every 6 hours
of IR OC/APAP (15 mg OC/650 mg APAP total for both). Peak plasma
levels of APAP following administration of the 1 tablet and 2
tablet dosing configurations of the extended release formulation
were observed (median T.sub.max) at 0.75 hours after dosing
compared with 0.5 hours after the first dose of the
commercially-available immediate release tablet (1 and 2 tablets).
Mean plasma concentrations of APAP were detectable through 36 hours
following all treatments and the mean t.sub.112 was approximately 4
to 7 hours across treatment groups. The extent of exposure (AUC) to
APAP following dosing with 1 and 2 tablets of the extended release
formulation increased proportionally with dose. Dose normalized
AUC.sub.0-t, AUC.sub.0-inf, and C.sub.max for APAP were comparable
across all treatment groups, indicating the bioavailability of APAP
was similar with ER OC/APAP (1 or 2 tablets once) to that with IR
OC/APAP (1 tablet twice), and also indicating dose proportionality
between 1 and 2 tablets for APAP with ER OC/APAP.
TABLE-US-00044 TABLE 37B APAP Pharmacokinetic Estimates (7.5/325)
Treatment C Treatment D Treatment A Treatment B IR OC/APAP IR
OC/APAP ER OC/APAP ER OC/APAP (1 tablet (2 tablets (1 tablet; (2
tablets; twice; twice; 7.5/325 mg) 15/650 mg) 15/650 mg.sup.c)
30/1300 mg.sup.c) Parameter (n = 33) (n = 33) (n = 33) (n =
27.sup.d) AUC.sub.0-t 15871 (4841) 32665 (10894) 33040 (9589) 69837
(22945) (ng h/mL) AUC.sub.0-inf 16995 (5073) 34836 (11067).sup.b
34236 (10126).sup.b 71949 (24234).sup.c (ng h/mL) C.sub.max (ng/mL)
2632 (918) 5230 (2086) 4878 (1545) 10741 (4123) T.sub.max (h).sup.a
0.75 (0.25-2.02) 0.75 (0.25-4.00) 0.50 (0.25-9.00) 0.50
(0.25-12.00) t.sub.lag (h).sup.a 0.00 (0.00-0.50) 0.00 (0.00-0.25)
0.00 (0.00-0.00) 0.00 (0.00-0.00) t.sub.1/2 (h) 5.33 (1.53) 6.88
(2.15).sup.b 4.41 (1.16).sup.b 5.76 (1.47).sup.c K.sub.el
(h.sup.-1) 0.1421 (0.0479) 0.1103 (0.0337).sup.b 0.1669
(0.0411).sup.b 0.1291 (0.0368).sup.c .sup.aMedian
(minimum-maximum). .sup.bN = 32 .sup.cN = 25
[0616] No dose-dumping was observed in any subject receiving the ER
formulation. The interindividual variability (CV %) for C.sub.max
of APAP was slightly more after administration of 1 and 2 tablets
of the ER formulation (35% and 40%, respectively) than for 1 tablet
of the commercially-available immediate release tablet (32%). The
interindividual variability (CV %) for AUC of APAP was less than
33% for all 3 treatments.
[0617] Both OC and APAP were rapidly absorbed under all conditions
with no lag in plasma concentrations. Both OC and APAP levels were
sufficiently high within 1 hour after administration of the
extended release formulation. Peak exposure to OC was 18% to 21%
lower for the ER formulation than for the commercially-available
immediate release tablet (1 tablet Q6 h). OC levels were sustained
over the proposed 12 h dosing interval. By 12 hours after dosing
with the extended release formulation, APAP plasma levels were less
than 20% of C.sub.max. Total exposure to both OC and APAP from the
extended release formulation was equivalent to that of 1 tablet of
the commercially-available immediate release tablet.
[0618] Adverse events were also monitored throughout the study.
Table 38 presents the most frequently occurring treatment-emergent
adverse events (TEAEs). Overall, 41 subjects (85%) reported
.gtoreq.1 TEAE; 44% were considered by the investigator to be mild
in intensity and 42% were considered to be moderate in intensity.
There were no serious adverse events. The most common TEAEs were
nausea, vomiting, somnolence, pruritus, and headache, which are
consistent with those associated with opioid therapy. A total of 19
subjects experienced vomiting and were discontinued early from the
study, as specified in the protocol. TEAEs were higher after
2-tablet dosing with IR OC/APAP (75.8%) than after 1-tablet or
2-tablet dosing with ER OC/APAP (25.6% and 51.2%, respectively) or
1-tablet dosing with IR OC/APAP (56.4%). Overall, TEAEs for ER
OC/APAP were similar to those for IR OC/APAP. Most individual
hematology and serum chemistry values were within the normal range.
All changes that were noted as abnormal were considered by the
investigator to not be clinically significant, except for elevated
bilirubin in 1 subject (2%), which was considered by the
investigator to be mild and possibly related to study
medication.
TABLE-US-00045 TABLE 38 Most Frequently Occurring
Treatment-Emergent Adverse Events IR OC/APAP IR OC/APAP ER OC/APAP
ER OC/APAP (1 tablet (2 tablets (1 tablet; (2 tablets; twice;
twice; 7.5/325 mg) 15/650 mg) 15/650 mg.sup.a) 30/1300 mg.sup.a)
Overall TEAE, n (%) (n = 39) (n = 41) (n = 39) (n = 33.sup.b) (N =
48) Any TEAE 10 (25.6) 21 (51.2) 22 (56.4) 25 (75.8) 41 (85.4)
Nausea 4 (10.3) 12 (29.3) 12 (30.8) 17 (51.5) 33 (68.8) Vomiting 2
(5.1) 7 (17.1) 4 (10.3) 6 (18.2) 19 (39.6) Somnolence 2 (5.1) 5
(12.2) 5 (12.8) 9 (27.3) 17 (35.4) Pruritus 0 3 (7.3) 5 5 (12.8) 12
(36.4) 16 (33.3) Headache 2 (5.1) 8 (19.5) 5 (12.8) 4 (12.1) 14
(29.2) Dizziness 1 (2.6) 4 (9.8) 4 (10.3) 7 (21.2) 13 (27.1)
.sup.aIR OC/APAP was dosed as 1 tablet every 6 hours and counted as
a single dose .sup.bCompleted all other treatment conditions
[0619] This study indicates that ER OC/APAP demonstrates a biphasic
delivery of oxycodone, with a rapid rise after dosing as seen with
IR OC/APAP, followed by controlled release that peaked at 3 to 4
hours post-dose and extended over 12 hours. APAP concentrations
rose rapidly and then tapered off at 7 to 12 hours post-dose. Lower
APAP concentrations at the end of the dosing period may reduce APAP
accumulation and thus lessen the possibility of the potential
hepatotoxic effects of APAP. Bioavailability of OC and APAP
throughout the dosing interval were comparable between ER OC/APAP
(1 or 2 tablets) and IR OC/APAP (1 tablet twice) under fasted
conditions. Dose proportionality with respect to AUC and C.sub.max
was observed between the 1-tablet and 2-tablet doses of ER OC/APAP.
ER OC/APAP was generally well tolerated, with the most frequently
reported TEAEs being nausea, headache, vomiting, and somnolence.
These findings demonstrate that ER OC/APAP yields plasma
concentrations comparable to those of IR OC/APAP with 12-hour
dosing, with a tolerability profile consistent with opioid
analgesics.
[0620] To further analyze the absorption of OC and APAP from the ER
formulation, the plasma concentrations of OC and APAP following
administration of 1 tablet of the ER formulation, 2 tablets of the
ER formulation, and the commercially-available immediate release
tablet were deconvolved using WinNonlin 5.2 (Pharsight).
Deconvolution evaluates in vivo drug release and delivery based on
data for a known drug input. Depending upon the type of reference
input information available, the drug transport evaluated will be
either a simple in vivo drug release (e.g., gastro-intestinal
release) or a composite form, typically consisting of an in vivo
release followed by a drug delivery to the general systemic
circulation. It can estimate the cumulative amount and fraction
absorbed over time for the subjects, given PK profile data and
dose. For a pure immediate release (IR) or an extended release (ER)
formulation the cumulative absorption plot shows a monoexponential
curve whereas for a bilayer formulation (IR+ER) a biexponential
(rapid phase followed by slower phase) absorption curve will be
observed. FIG. 23 and FIG. 24 present the deconvolution plots for
OC and APAP, respectively. For each, there is an early rapid phase
of absorption that is followed by a later slower phase of
absorption from the ER formulation.
Example 11
Clinical Pharmacokinetic Analysis of an Extended Release
Formulation of 7.5 mg Oxycodone/325 mg Acetaminophen--Multiple
Doses
[0621] An open-label, randomized, 3-period crossover study was
performed to evaluate the steady-state PK, bioavailability, and
safety of the extended release formulation containing 7.5 mg OC/325
mg APAP in healthy subjects (see selected example from Chart No.
1). The PK and bioavailability of the ER formulation administered
as 1 or 2 tablets every 12 hours for 4.5 days (9 doses) was
compared to the commercially-available immediate release tablet
(immediate release 7.5 mg OC/325 mg APAP) administered as 1 tablet
every 6 hours for 4.5 days (18 doses) under fasted conditions (10
hours for the first dose on Days 1 and 5; at least 1 hour for all
other doses). This study was conducted in 48 male and female
subjects, with equal gender distribution.
[0622] The PK behavior of OC on Study Day 1 (see Table 39) was
similar to that observed in the single dose study (see Example 10).
There was no lag (median t.sub.lag 0 hours) in the absorption of OC
following administration of the ER formulation (1 or 2 tablets) and
the commercially-available immediate release tablet, and no
dose-dumping was observed for any subject. Peak plasma levels were
observed at 3 hours after administration of 1 and 2 tablets of the
ER formulation and at 1 hour after the second dose of the
commercially-available immediate release tablet (FIG. 25). On Day
1, interindividual variability (% CV) in the C.sub.max for OC was
slightly higher for 1 tablet (29%) than for 2 tablets (23%) of the
ER formulation or the commercially-available immediate release
tablet (up to 22%). The variability in the AUC.sub.0-12hr for OC
was comparable between all 3 treatments (21% to 23%). Minimum
(trough) plasma concentrations (Cmin) of OC achieved steady-state
levels by Day 4 for 1 tablet of the ER formulation and the
commercially-available immediate release tablet and by Day 3 for 2
tablets of the ER formulation. Trough levels of OC on Days 2
through 5 for 2 tablets of the ER formulation were comparable to
those observed for the commercially-available immediate release
tablet.
TABLE-US-00046 TABLE 39 Oxycodone Pharmacokinetic Estimates - Day 1
Treatment C Commercially- available Treatment A Treatment B
immediate ER Formulation ER Formulation release tablet (1 Tablet
Q12h) (2 Tablets Q12h) (1 Tablet Q6h) Mean (SD) Mean (SD) Mean (SD)
Parameter (N = 33) (N = 33) (N = 33) AUC.sub.0-12 h 66.93 (15.14)
135.89 (30.81) 141.73 (29.78) (ng h/mL) C.sub.max (ng/mL) 8.34
(2.37) 17.05 (3.97) 21.93 (4.80) T.sub.max (h).sup.a 3.00
(0.75-7.00) 3.00 (0.50-5.92) 7.00 (0.50-8.00) t.sub.lag (h).sup.a
0.00 (0.00-0.50) 0.00 (0.00-0.32) 0.00 (0.00-0.25) .sup.aMedian
(minimum-maximum).
[0623] On Day 5 (see Table 40), steady state was achieved and the
median T.sub.max.sup.ss was observed at 2 hours following 1 tablet
or 2 tablets of the ER formulation and at 30 min following the
second daily dose of the commercially-available immediate release
tablet. Maximum observed plasma concentrations at steady-state
(C.sub.max.sup.ss) for OC for the 1 and 2 tablet dosing
configurations of the ER formulation were not equivalent to the
commercially-available immediate release tablet. On Day 5,
interindividual variability (% CV) in C.sub.max.sup.ss and
AUC.sub.0-12h.sup.ss for OC was comparable between all 3 treatments
(up to 29%). The degree of fluctuation (DFL) in and the swing of
plasma concentrations for the ER formulation over the last 12 hour
dosing interval on Day 5 were 15% to 22% less than that observed
for the commercially-available immediate release tablet.
TABLE-US-00047 TABLE 40 Oxycodone Pharmacokinetic Estimates - Day 5
Treatment C Commercially- available Treatment A Treatment B
immediate ER Formulation ER Formulation release tablet (1 Tablet
Q12h) (2 Tablets Q12h) (1 Tablet Q6h) Mean (SD) Mean (SD) Mean (SD)
Parameter (N = 33) (N = 33) (N = 33) AUC.sub.0-12 h.sup.ss 102.36
(29.30) 208.59 (59.28) 208.93 (57.30) (ng h/mL) C.sub.av.sup.ss
(ng/mL) 8.53 (2.44) 17.38 (4.94) 17.41 (4.78) C.sub.max.sup.ss
(ng/mL) 12.67 (3.48) 25.67 (7.49) 30.50 (8.91) C.sub.min.sup.ss
(ng/mL) 4.06 (1.40) 8.98 (3.52) 8.78 (3.17) DFL (%) 101.72 (14.14)
97.17 (18.80) 126.83 (27.93) Swing 2.23 (0.64) 2.03 (0.70) 2.67
(0.92) T.sub.max.sup.ss (h).sup.a 2.00 (0.50-10.00) 2.00
(0.50-7.00) 6.50 (0.50-8.02) t.sub.1/2 (h).sup.c 5.46 (1.24) 6.11
(1.46) 5.47 (1.70).sup.b K.sub.el (1/h).sup.c 0.1326 (0.0269)
0.1199 (0.0291) 0.1387 (0.0418).sup.b .sup.aMedian
(minimum-maximum). .sup.bN = 32 .sup.cDays 5 to 7.
[0624] The PK behavior of APAP on Study Day 1 (see Table 41) was
similar to that observed in the single dose study (see Example 10).
Acetaminophen was rapidly absorbed following a single dose of 1 or
2 tablets of the ER formulation and in a similar fashion to the
commercially-available immediate release tablet. (FIG. 26). There
was no lag in plasma concentrations following any of the 3 dosing
regimens (median t.sub.lag 0 hours), and no dose-dumping was
observed for any subject. Peak APAP plasma concentrations were
observed 30 to 45 minutes after administration of 1 or 2 tablets of
the ER formulation and at 30 minutes after the first dose of the
commercially-available immediate release tablet on Day 1. The
C.sub.max for APAP occurred following the first 325 mg dose of the
commercially-available immediate release tablet, rather than after
the second dose. Dose proportionality for C.sub.max and
AUC.sub.0-12h was observed over the range of 325 mg to 650 mg APAP
after a single administration of 1 or 2 tablets of the ER
formulation. The C.sub.min of APAP achieved steady-state levels by
Day 4 for 1 tablet and by Day 2 for 2 tablets of the ER formulation
and for the commercially-available immediate release tablet. Trough
levels of APAP on Days 2 through 5 for 2 tablets of the ER
formulation were comparable to those observed for the
commercially-available immediate release tablet. On Day 1,
interindividual variability (% CV) in C.sub.max and AUC.sub.0-12hr
for APAP was comparable between all 3 treatments (31% or less).
TABLE-US-00048 TABLE 41 APAP Pharmacokinetic Estimates - Day 1
Treatment C Commercially- available Treatment A Treatment B
immediate ER Formulation ER Formulation release tablet (1 Tablet
Q12h) (2 Tablets Q12h) (1 Tablet Q6h) Mean (SD) Mean (SD) Mean (SD)
Parameter (N = 33) (N = 33) (N = 33) AUC.sub.0-12 h 12192 (3331)
24141 (6436) 24884 (6656) (ng h/mL) C.sub.max (ng/mL) 2631 (815)
5245 (1473) 5146 (1553) T.sub.max (h).sup.a 0.55 (0.25-3.00) 0.75
(0.25-2.00) 0.50 (0.25-8.00) t.sub.lag (h).sup.a 0.00 (0.00-0.25)
0.00 (0.00-0.25) 0.00 (0.00-0.00) .sup.aMedian
(minimum-maximum).
[0625] On Day 5 of the study, median T.sub.max.sup.ss for APAP was
observed at 30 minutes following 1 or 2 tablets of the ER
formulation and at 30 minutes following the first daily dose of the
commercially-available immediate release tablet (see Table 42).
Acetaminophen concentrations following administration of 325 mg or
650 mg APAP (1 or 2 tablets) Q12 h were proportional to dose. The
DFL in and swing of plasma APAP levels for the ER formulation were
equivalent to the commercially-available immediate release tablet.
On Day 5, interindividual variability (% CV) in C.sub.max.sup.ss
for APAP was slightly higher following administration of 2 tablets
of the ER formulation (33%) than the % CV seen for 1 tablet of the
ER formulation and the commercially-available immediate release
tablet (.about.27%). Interindividual variability in
AUC.sub.0-12h.sup.ss for APAP was comparable between all 3
treatments (up to 27%).
TABLE-US-00049 TABLE 42 APAP Pharmacokinetic Estimates - Day 5
Treatment C Commercially- available Treatment A Treatment B
immediate ER Formulation ER Formulation release tablet (1 Tablet
Q12h) (2 Tablets Q12h) (1 Tablet Q6h) Mean (SD) Mean (SD) Mean (SD)
Parameter (N = 33) (N = 33) (N = 33) AUC.sub.0-12 h.sup.ss 15307
(4092) 28512 (7714) 28719 (7023) (ng h/mL) C.sub.av.sup.ss (ng/mL)
1276 (341) 2376 (643) 2393 (585) C.sub.max.sup.ss (ng/mL) 3117
(840) 5872 (1932) 5968 (1639) C.sub.min.sup.ss (ng/mL) 474.67 (163)
870.42 (336) 922.58 (321) DFL (%) 212.08 (52.29) 218.06 (81.14)
213.79 (50.53) Swing 5.95 (2.04) 6.63 (3.61) 5.94 (2.24)
T.sub.max.sup.ss (h).sup.a 0.50 (0.25-3.00) 0.50 (0.25-3.02) 0.50
(0.25-8.02) t.sub.1/2 (h).sup.c 5.60 (1.35).sup.b 7.47 (2.89) 5.74
(2.98).sup.b K.sub.el (1/h).sup.c 0.1308 (0.0317).sup.b 0.1026
(0.0292) 0.1416 (0.0515).sup.b .sup.aMedian (minimum-maximum).
.sup.bN = 31 .sup.cDays 5 to 7.
[0626] Both OC and APAP were rapidly absorbed under all conditions
with no lag in plasma concentrations. Both OC and APAP levels were
sufficiently high within 1 hour after administration of the ER
formulation as a single dose and at steady-state. OC levels were
sustained over the proposed 12 h dosing interval. Plasma APAP
concentrations decreased to below 1,000 ng/mL between doses of the
ER formulation, thus minimizing the chances of its accumulation and
the possibility of hepatotoxicity. Total exposure to both OC and
APAP from the ER formulation was equivalent to that of the
commercially-available immediate release tablet.
Example 12
Clinical Evaluation of the Safety and Analgesic Efficacy of an
Extended Release Formulation of Oxycodone and Acetaminophen for
Acute Pain
[0627] Pain relief for acute post-surgical pain requires
immediate-release (IR) compounds acting within 1 hour of
administration. These IR compounds, however, have a short half-life
and require frequent administration; this is inconvenient to
patients and leads to poor compliance. Such patients may benefit
from an extended-release (ER) oral formulation of oxycodone
hydrochloride (OC) and acetaminophen (APAP) that is designed to (1)
provide the immediate-release of each drug to attain rapid
therapeutic levels (within 1 hour of dosing) and (2) provide
continuous release of each drug to maintain the plasma levels of
each drug within therapeutic windows for sustained analgesia (up to
12 hours). Furthermore, combining analgesics with distinct
mechanisms of action provides maximum efficacy while reducing the
toxicity of each agent, as the amount of OC and APAP can remain
within the lower, safer end of their therapeutic windows. This ER
formulation may provide the advantages of both immediate and
prolonged pain relief from two analgesic compounds, potentially
offering greater convenience to patients and greater dosing
compliance.
[0628] Accordingly, a randomized, double-blind, placebo-controlled,
phase 3 study was conducted to demonstrate the efficacy of repeated
doses of 15 mg OC/650 mg APAP (see selected example from Chart No.
1, which may be referred to in this example as the "study
medication") versus placebo, and to determine the safety and
tolerability of multiple oral doses of the OC/APAP formulation
administered to subjects with acute postoperative, moderate to
severe pain.
[0629] In this clinical trial, ER OC/APAP was studied in an
established acute pain model in patients undergoing a first
metatarsal bunionectomy. Medication effects were evaluated 48 hours
post-procedure (double-blind) and continued throughout a voluntary
open-label treatment period (up to 14 days). Patients aged 18 to 75
years undergoing unilateral, first metatarsal bunionectomy who
reported at least moderate or severe pain intensity and numeric
rating scale score of .gtoreq.4 (out of 10) between the hours of
4:00 AM and 12:00 PM (after cessation of intravenous popliteal
nerve block) on the first postoperative day were eligible for the
study.
[0630] FIG. 93 presents a summary of the study design. The study
was conducted in the following phases: 1) pre-treatment phase
consisting of a) screening, b) surgery, and c)
recovery/qualification periods; 2) double-blind phase consisting of
a single-dose period followed by a multiple-dose period which
begins with either (i) the request of the second dose of study
medication, or (ii) 12 hours after the first dose of study
medication; and 3) a voluntary open-label extension ("OLE")
phase.
[0631] The subjects consisted of males and females who were of good
general health, and had undergone a primary unilateral first
metatarsal bunionectomy. Each subject participated in the
double-blind study for up to 40 days, including a screening period
of up to 30 days, a surgical period of 1 day, a blinded dosing
phase of 2 days, and, for those not entering the OLE phase, a
follow-up period of about 7 days. The OLE phase lasted up to 14
days, bringing the total participation time to approximately 54
days.
[0632] The single-dose period of the double-blind phase evaluated
the onset and duration of analgesia of a single dose of extended
release 15 mg OC/650 mg APAP (as two 7.5/325 tablets) versus
placebo. The time from the initial dose of study medication to the
onset of perceptible pain relief and to the onset of meaningful
pain relief was measured. The subjects provided additional pain
assessments (e.g., pain intensity scores measured using the 11
point NPRS scale at regular intervals). The use of supplemental
analgesia was permitted (i.e., ibuprofen 400 mg up to 6 times per
day [2400 mg/d]) during the double-blind and open-label phases of
the study.
[0633] The multiple-dose period of the double-blind phase evaluated
the analgesic effects of multiple doses of extended release 15 mg
OC/650 mg APAP versus placebo with subjects dosed regularly every
12 hours for 48 hours. The multiple dose period began either upon
administration of the second dose after the subject's request for
additional pain relief or 12 hours after the first dose of study
medication. Pain relief and intensity will be among the data
measured in this arm of the study.
[0634] After completion of study evaluations 48 hours after the
second dose of study medication, subjects were encouraged to enter
the open-label extension phase of the study. During this time they
were provided with doses of 15 mg OC/650 mg APAP to be taken every
12 hours until the study medication was no longer needed, for up to
14 days. The open-label extension phase (starting 48 hours after
the second dose) evaluated the safety profile as determined by
adverse events (AE) and evaluated subject satisfaction with
analgesic effects. Eligibility criteria for the open-label
extension phase of the study included completing the double-blind
phase of the study; having a pain intensity score at completion of
the double-blind phase of the study, but no later than 52 hours
after receiving the first dose of study drug; signing an open-label
extension consent form prior to surgery; and agreeing to
participate in the open-label extension phase of the study. The
open-label phase lasted up to 14 days, with clinic visits at days 7
and 14 (.+-.1 day), followed by a telephone call 7 days (.+-.2
days) after the last dose.
[0635] Exclusion criteria included any medical condition that might
decrease study compliance or alter the absorption, distribution,
metabolism, or excretion of the study drug (e.g., severe chronic
diarrhea, chronic constipation, irritable bowel syndrome, or
unexplained weight loss); gastric bypass surgery or gastric band;
history of intolerance to short-term opioid use; and treatment with
study drug or bunionectomy in previous 3 months.
[0636] Safety and tolerability assessments were conducted
throughout the open-label phase of the study and included physical
examinations, measurement of vital signs (e.g., sitting blood
pressure, pulse rate, and temperature), and clinical laboratory
tests (i.e., chemistry, hematology, and urinalysis). Adverse events
were collected at each visit and the 7-day follow-up phone call.
Global assessment of patient satisfaction was evaluated at 48 hours
or early termination for the blinded-dosing phase and at every
clinic visit for the open-label phase. The study assessed the
patient's satisfaction with treatment across 5 dimensions, such as
ease of administration and level of pain relief, on a categorical
scale (i.e., very satisfied, satisfied, neither satisfied nor
dissatisfied, dissatisfied, or very dissatisfied).
[0637] Descriptive statistics were summarized for baseline
characteristics and global assessment of satisfaction. Medication
adherence and treatment-emergent adverse events (TEAEs) were
summarized using frequencies and percentages. Summary statistics
for actual values and changes from baseline were calculated for the
physical examination findings, laboratory test results, vital
signs, and pulse oximetry, and a shift analysis examined
categorical changes from baseline to various time points.
[0638] Pain intensity was rated with an 11-item numerical rating
scale (0=no pain; 10=the worst pain imaginable). The primary
outcome measure was the summed pain intensity difference over the
first 48 hours (SPID48). SPID48 was calculated as the sum of
time-weighted pain intensity difference (PID) scores over the first
48 hours (PID=[baseline pain intensity score]-[pain intensity score
at time point of interest]). Secondary outcome measures included
pain intensity scores, PID associated with each pain intensity
score, and SPID at multiple time points over 48 hours; total pain
relief (TOTPAR) at multiple time points over the first 48 hours;
and the time to perceptible, meaningful, and confirmed pain relief.
To reduce the confounding effects of censored (unusable) pain
scores due to use of supplemental analgesia (i.e., ibuprofen), PID
was estimated using multiple imputation techniques and 6-hour
censoring, respectively. The double stopwatch method was used to
determine time to onset of pain relief. Global assessment of
subject satisfaction was conducted during the study. Safety and
tolerability assessments were conducted throughout the double-blind
and open-label phases of the study; adverse events were assessed at
follow-up, and any significant measures were followed-up as
medically indicated.
[0639] A total of 329 patients were enrolled and received dose of
study drug in the blinded-dosing phase of the study 166 patients
received ER OC/APAP; 163 received placebo. 293 patients (89.1%)
completed the double-blind phase of the study. 146 patients (49.8%;
prior ER OC/APAP, n=77; prior placebo, n=69) who completed the
double-blind phase of the study entered the open-label phase of the
study, with 129 patients (88.4%) completing the open-label
extension. 145 patients attended the 1-week follow-up visit, and 36
patients attended the 2-week follow-up visit. Demographic
characteristics of the open-label safety population were generally
similar between groups. During the open-label dosing phase, 120
patients (82.2%) received .+-.20% of the expected doses.
[0640] Efficacy analyses were performed on a modified
intent-to-treat (mITT) population (N=303) randomized to treatment
with either ER OC/APAP (n=150) or placebo (n=153). Demographic and
baseline characteristics of the mITT population were generally
similar between groups. The mean baseline pain intensity score for
the mITT population was 6.2 (SD=1.7) for the ER OC/APAP treatment
population and 6.0 (SD=1.5) for the placebo population.
[0641] The superior efficacy of the study medication compared to
the placebo in the treatment of acute pain after bunionectomy was
demonstrated consistently across a variety of validated pain
measures. The primary endpoint, the sum of the pain intensity
difference over the 48-hour blinded period, was statistically
significantly greater in the study medication group compared to the
placebo group. Indeed, the subjects treated with the study
medication had less pain than the placebo-treated subjects. The
multiple imputation mean summed pain intensity difference over the
first 48 hours ("SPID.sub.48") was significantly greater for the
study medication group than the placebo group, namely, 114.9 versus
66.9, with a treatment difference of 48.0, which was statistically
significant (P<0.001).
[0642] Decrease in pain intensity scores over time are shown in
FIG. 94 (for hours 0 to 2) and FIG. 95 (for hours 0 to 48). Mean
PID for ER OC/APAP was numerically superior beginning at the
earliest time point measured (15 min); statistical significance was
reached 30 minutes after the first dose of study drug (P<0.02).
Mean SPID over 0-4 (6.5), 0-12 (13.0), 0-24 (27.7), and 0-36 hours
(39.7) were all statistically significant for ER OC/APAP versus
placebo (P<0.001 for all comparisons). Furthermore, as shown in
Table 100, mean TOTPAR over 0-4, 0-12, 0-24, 0-36, and 0-48 hours
were all significantly greater for ER OC/APAP versus placebo.
TABLE-US-00050 TABLE 100 Total Pain Relief Over 0-4, 0-12, 0-24,
0-36, and 0-48 Hours Treatment TOTPAR ER OC/APAP Placebo Difference
P Interval (n = 150).sup.a (n = 153).sup.a (95% CI) Value 0-4 h 6.8
(0.4) 3.4 (0.4) 3.4 (2.4-4.4) <0.001 0-12 h 16.5 (0.9) 11.2
(0.8) 5.3 (2.9-7.7) <0.001 0-24 h 38.4 (1.7) 26.8 (1.6) 11.6
(7.1-16.2) <0.001 0-36 h 64.2 (2.5) 47.5 (2.5) 16.8 (9.8-23.8)
<0.001 0-48 h 91.3 (3.5) 70.9 (3.4) 20.5 (11.0-30.0) <0.001
.sup.aMean (SE) CI = confidence interval
[0643] The proportion of patients with .gtoreq.30% reduction in
pain intensity score at different times during the first 2 hours of
treatment is shown in FIG. 96. The proportion of 30% responders was
significantly higher with ER OC/APAP than with placebo from as
early as 30 minutes after the first dose, and the difference
increased over the subsequent 90 minutes. This fast onset of action
was further demonstrated by the mean TOTPAR values over the first 4
hours (Table 100), as well as by the times to perceptible and
confirmed perceptible pain relief.
[0644] More patients receiving ER OC/APAP experienced perceptible,
meaningful, and confirmed perceptible pain relief. As shown in
Table 101, median time to pain relief was significantly shorter for
ER OC/APAP compared with placebo.
TABLE-US-00051 TABLE 101 Median Time to Onset of Perceptible,
Confirmed Perceptible, and Meaningful Pain Relief ER OC/ APAP
Placebo Time, min (n = 150) (n = 153) P Value To perceptible pain
relief 33.56 43.63 <0.001 To confirmed perceptible pain relief
47.95 NE <0.001 To meaningful pain relief 92.25 NE <0.001 NE
= could not be estimated due to less than half the subjects
experiencing confirmed or meaningful pain relief.
[0645] At the end of the double-blind phase, more patients
indicated they were either "satisfied" or "very satisfied" with
time taken for medication to work and level of pain relief by pain
medication for ER OC/APAP compared with placebo. FIG. 97 presents
the percentage of patients "satisfied" or "very satisfied" on items
of the global assessment of satisfaction at 48 hours. As would be
expected, there were no differences between groups on ease of
taking, frequency of taking, or amount of medication taken.
[0646] Overall, during the blinded-dosing phase of the study, 37.7%
of patients in the safety population (124/329) experienced a
treatment-emergent adverse event (TEAE). The most common TEAEs
reported during the blinded-dosing phase of the study are
summarized in Table 102. As expected for this class of medication,
a greater percentage of patients receiving ER OC/APAP reported
nausea (30.7% vs 5.5%), dizziness (13.3% vs 1.2%), headache (9.6%
vs 4.9%), skin and subcutaneous disorders (9.0% vs 4.3%), vomiting
(9.0% vs 0%), and somnolence (3.6% vs 0.6%) compared with patients
receiving placebo, respectively. Constipation was reported by a
small percentage of patients receiving either ER OC/APAP or placebo
(4.2% vs 3.1%, respectively). One patient in the group receiving ER
OC/APAP reported a severe TEAE (headache), and no serious adverse
events were reported during the blinded-dosing phase of the
study.
TABLE-US-00052 TABLE 102 Summary of Treatment-Emergent Adverse
Events Occurring in >3% of Patients Treatment-Emergent ER
OC/APAP Placebo All Patients Adverse Event, n (%) (n = 166) (n =
163) (N = 329) Any TEAE 89 (53.6) 35 (21.5) 124 (37.7) Nausea 51
(30.7) 9 (5.5) 60 (18.2) Dizziness 22 (13.3) 2 (1.2) 24 (7.3)
Headache 16 (9.6) 8 (4.9) 24 (7.3) Skin and subcutaneous 15 (9.0) 7
(4.3) 22 (6.7) tissue disorders Vomiting 15 (9.0) 0 15 (4.6)
Constipation 7 (4.2) 5 (3.1) 12 (3.6) Somnolence 6 (3.6) 1 (0.6) 7
(2.1)
[0647] Overall, the subjects that were administered the study
medication during the blinded dosing phase had less pain, greater
pain relief, less need for rescue medication, and rated the study
medication more highly as a pain reliever. The result of this study
therefore demonstrated that the study medication was shown to
provide rapid, significant, and consistent analgesic efficacy over
the 12-hour dosing interval, with pain relief satisfaction
statistically significantly better than the placebo over the
48-hour blinded treatment period. The majority of subjects were
also very satisfied in their global assessment of therapy during
the OLE phase. The safety findings indicate that study medication
is well tolerated, with a safety profile desirable from a low-dose
opioid/APAP treatment.
[0648] Table 103 presents a summary of the treatment-emergent
adverse events (TEAEs) occurring during the open label phase. A
total of 64 patients (43.8%) experiences .gtoreq.1 TEAE. The most
frequently reported TEAEs were primarily gastrointestinal related
(nausea, vomiting, constipation) and central nervous system-related
(somnolence, headache, dizziness).
TABLE-US-00053 TABLE 103 Treatment-Emergent Adverse Events
Occurring During the Open-Label Phase Prior Prior Double-Blind
Double-Blind All Treatment-Emergent ER OC/APAP Placebo Patients
Adverse Event, n (%) (n = 77) (n = 69) (N = 146) Any TEAE 25 (32.5)
39 (56.5) 64 (43.8) Nausea 8 (10.4) 18 (26.1) 26 (17.8) Vomiting 3
(3.9) 8 (11.6) 11 (7.5) Constipation 4 (5.2) 5 (7.2) 9 (6.2)
Somnolence 1 (1.3) 6 (8.7) 7 (4.8) Headache 4 (5.2) 2 (2.9) 6 (4.1)
Dizziness 2 (2.6) 4 (5.8) 6 (4.1) Peripheral edema 3 (3.9) 1 (1.4)
4 (2.7) Pruritus 1 (1.3) 3 (4.3) 4 (2.7) Infection 1 (1.3) 3 (4.3)
4 (2.7)
[0649] One patient reported 3 severe TEAEs, and 1 patient reported
a serious adverse event (i.e., deep vein thrombosis determined by
the investigator to be unrelated to treatment with the study drug).
Changes from baseline in laboratory values (i.e., hematology, serum
chemistry, and urinalysis) were generally small and were similar
between treatment groups during double-blind periods and similar
between the double-blind and open-label periods. Six patients
(4.1%) had alanine aminotransferase and/or aspartate
aminotransferase times the upper limit of normal values at least
once during the study. Total bilirubin remained within the normal
reference range in all 6 cases. None met Hy's Law criteria.
[0650] Table 104 presents the vital sign measures and changes from
baseline after 7 days of open-label treatment. Vital signs during
the open-label phase were normal in >90% of patients at any
visit. During the open-label phase, .ltoreq.1.4% of patients had
shifts from normal to abnormal oxygen saturation at any time
point.
TABLE-US-00054 TABLE 104 Vital Sign Measures and Changes From
Baseline After 7 Days of Open-Label Treatment Baseline OL Visit
Change Value Day 7 From Vital Sign (n = 146) (n = 145) Baseline
Systolic blood pressure, mmHg Mean (SD) 117.3 (14.12) 120.6 (14.4)
3.4 (12.34) Median 116.0 120.0 3.0 Diastolic blood pressure, mmHg
Mean (SD) 73.2 (9.31) 75.2 (9.07) 2.1 (8.45) Median 72.0 74.0 2.0
Heart rate, beats/min Mean (SD) 73.9 (10.81) 74.1 (11.62) 0.2
(10.99) Median 74.0 74.0 -1.0 Respiratory rate, breaths/min Mean
(SD) 16.3 (1.94) 15.8 (1.68) -0.5 (2.52) Median 16.0 16.0 0.0 Body
temperature, .degree. C. Mean (SD) 36.66 (0.50) 36.40 (0.54) -0.26
(0.58) Median 36.70 36.50 -0.20 Oxygen saturation, % Mean (SD) 97.6
(1.69) 98.0 (1.60) 0.4 (1.76) Median 98.0 98.0 0.0 * By Day 14,
very few patients required pain medications (n = 36); therefore,
data from n = 145 completing day 7 are shown above.
[0651] FIG. 98 presents the proportion of patients "satisfied" or
"very satisfied" with ER OC/APAP after 7 or 14 days of open-label
phase treatment, according to five different measures. At the 7-day
follow-up, more than 88% (of 144 patients) indicated they were
"very satisfied" or "satisfied" on all measures. At the 14-day
follow-up, more than 83% (of 36 patients) indicated they were "very
satisfied" or "satisfied" on all measures.
[0652] The results of this study demonstrate that multiple-dose
administration of ER OC/APAP was generally well tolerated. The most
frequently reported adverse events were consistent with those seen
with other opioids in general, and specifically, oxycodone. Shifts
in laboratory test results, vital signs, and oxygen saturation were
generally small and not clinically significant. All changes in
clinical laboratory tests and vital signs that were outside of the
defined reference range(s) were not clinically significant
according to the investigator. More than 80% of patients were very
satisfied or satisfied with every measure of treatment assessed,
including 94.4% for ease of administration, 86.1% for time for the
medication to work, and 83.3% for level of pain relief.
Example 13
Clinical Evaluation of the Safety and Efficacy of an Extended
Release Formulation of Oxycodone and Acetaminophen for Chronic
Pain
[0653] A multi-center, phase 3, open label safety study of doses of
extended release 15 mg OC/650 mg APAP (see selected example from
Chart No. 1) administered at 12 hour intervals for up to 35 days in
a patient population having pain associated with osteoarthritis
(OA) of the knee or hip or chronic low back pain (CLBP) were
conducted. The primary objective of the study was to determine the
safety and tolerability of doses of extended release 15 mg OC/650
mg APAP for up to 35 days of use. Secondary objectives such as pain
relief, changes in pain intensity, and pain-related quality of life
were also assessed.
[0654] Participants in the study were adults with clinical
diagnoses of osteoarthritis of the knee or hip, with moderate to
severe pain intensity despite chronic use of stable doses of
nonopioid or opioid analgesics; or chronic low back pain that was
moderate to severe in intensity and present for several hours a day
for months. Patients transitioned from nonopioid analgesics to
opioid combination therapy. A 3-day washout period was required for
all patients taking analgesic medications.
[0655] FIG. 99 presents a summary of the study design. The study
included a screening period of up to two weeks followed by a 3-day
washout period. ER OC/APAP was administered as 2 tablets every 12
hours for up to 35 days. Weekly clinic visits were used to assess
safety and tolerability, as well as efficacy. Assessments occurred
at >2 hours after dosing.
[0656] Subjects enrolled in the study were treated with 2 tablets
of extended release 7.5 mg OC/325 mg APAP every 12 hours (Q12 h)
for between 10 days and 35 days. Subjects initially took 1 tablet
of 7.5 mg OC/325 mg APAP under clinic supervision. Subjects were
observed for opioid tolerability symptoms. Subjects who experience
opioid tolerability symptoms, or moderate to severe adverse events,
were discontinued from the study. Subjects who did not experience
opioid tolerability symptoms, or moderate to severe adverse events,
were given a second tablet of 7.5 mg OC/325 mg APAP under clinic
supervision. If subjects still did not experience opioid
tolerability symptoms, or moderate to severe adverse events, they
were sent home with supplies for dosing with 2 tablets of 7.5 mg
OC/325 mg APAP Q12 h for one week. If subjects did experience
opioid tolerability symptoms, or moderate to severe adverse events,
they were sent home with supplies for dosing with 1 tablet of 7.5
mg OC/325 mg APAP Q12 h for one week. Supplemental analgesia,
consisting of 400 mg ibuprofen (two 200 mg tablets), could be taken
as needed every 4 to 6 hours to manage breakthrough pain (2400 mg
maximum daily).
[0657] Subjects that continued in the study beyond one week took 2
tablets Q12 h for up to a total of 35 days, during which time they
returned to the clinic for subsequent assessments of safety and
efficacy. After the Day 36 visit, subjects were instructed to
return to their pre-study medication. Subjects whose pain subsided
prior to the Day 36 visit, or who discontinued the study medication
for other reasons were instructed to return any remaining study
medication.
[0658] The following safety assessments were conducted at baseline
and weekly throughout the study period: treatment adherence,
treatment-emergent adverse events (TEAEs), vital signs, pulse
oximetry, and liver function tests. Additional laboratory tests
(chemistry, hematology, and urinalysis) were performed at screening
and the final visit. The following efficacy assessments were
conducted for patients in the study: Brief Pain Inventory (BPI) for
all patients; Western Ontario and McMaster Universities Arthritis
Index (WOMAC) questionnaire for patients with osteoarthritis;
Roland-Morris Disability Questionnaire (RMDQ) for patients with
chronic low back pain.
[0659] Summary statistics, frequency counts, and percentages were
calculated for baseline demographics, duration of exposure, and
TEAEs. Shift analysis examining changes from baseline to end of
treatment were performed for physical examination findings and
laboratory test results. For vital signs and pulse oximetry, actual
measurements at baseline and at end of treatment (taken at least 2
hours post-dose), along with change from baseline, were summarized.
Summary statistics for actual values and changes from baseline were
calculated for the secondary efficacy assessments.
[0660] FIG. 100 provides a summary of the patient disposition in
the study. Of the 376 patients enrolled, 75.8% completed the study.
The most common reason for discontinuation was TEAE. Per protocol,
any patient who experienced emesis or moderate or severe nausea
within 4 hours of dosing was discontinued. Mean duration of ER
OC/APAP exposure was 29.2 days, with duration of exposure
.gtoreq.10 days for 82.4% of patients. 94.1% of patients received
.+-.20% of the expected doses.
[0661] Overall, 62.5% of patients experienced .gtoreq.1 TEAE. TEAEs
that occurred in .gtoreq.5% of patients were nausea, vomiting,
dizziness, somnolence, constipation, pruritus, and headache. Table
105 presents a summary of the TEAE events. Most TEAEs were rated by
the investigator to be mild or moderate in intensity; 17 patients
reported a total of 22 severe TEAEs, of whom 10 patients
experienced .gtoreq.1 severe gastrointestinal event (nausea, n=6;
vomiting, n=5; and constipation, n=1). A total of 4 patients
experienced .gtoreq.1 severe adverse event (as rated by the
investigator).
TABLE-US-00055 TABLE 105 Treatment-Emergent Adverse Events
Occurring in .gtoreq.5% of Patients, Safety Population
Treatment-Emergent OA, Hip OA, Knee CLBP Total Adverse Event, n (%)
(n = 12) (n = 129) (n = 235) (N = 376) Nausea 2 (16.7) 29 (22.5) 56
(23.8) 87 (23.1) Vomiting 2 (16.7) 17 (13.2) 38 (16.2) 57 (15.2)
Dizziness 3 (25.0) 20 (15.5) 33 (14.0) 56 (14.9) Somnolence 1 (8.3)
11 (8.5) 31 (13.2) 43 (11.4) Constipation 1 (8.3) 14 (10.9) 27
(11.5) 42 (11.2) Pruritus 0 (0) 8 (6.2) 19 (8.1) 27 (7.2) Headache
0 (0) 6 (4.7) 13 (5.5) 19 (5.1) CLBP = chronic low back pain; OA =
osteoarthritis.
[0662] The majority of patients (>85% on 31 of 35 measures) had
normal hematology, chemistry, and urinalysis values at end of
treatment; few subjects shifted from normal to abnormal values.
Table 106 presents a summary of the changes in vital signs or pulse
oximetry. Changes in physical examination findings, vital signs,
and oxygen saturation were not clinically significant. One patient
(0.2%) was found to have hypopnea that was considered related to
study medication and resulted in discontinuation.
TABLE-US-00056 TABLE 106 Changes in Vital Signs and Pulse Oximetry,
All Participants End of Baseline Treatment Measure, Mean (SD) (N =
376) (n = 367) Change Systolic blood pressure, 125.9 (13.7) 124.9
(13.0) -0.9 (13.0) mmHg Diastolic blood pressure, 78.0 (9.1) 77.5
(8.8) -0.5 (9.0) mmHg Heart rate, beats/min 74.5 (9.7) 73.2 (10.4)
-1.2 (9.6) Respiratory rate, breaths/ 16.0 (2.0) 16.1 (2.0) 0.1
(1.6) min Body temperature, C..degree. 36.7 (0.4) 36.6 (0.4) -0.03
(0.4) Oxygen saturation, % 97.1 (1.6) 97.1 (1.7) -0.04 (1.6)
[0663] Shifts in liver function test results from normal at
baseline to elevated at the end of treatment were observed in a
small number of patients. 25 (6.9%) patients had shifts from normal
to elevated ALT (alanine aminotransferase); 18 (5.0%) experienced a
shift from normal to elevated AST (aspartate aminotransferase); and
2 (0.6%) patients had shifts from normal to elevated bilirubin. 4
(1.1%) patients had either ALT and/or AST values >5 times the
upper limit of normal (ULN) at some point during the study; none
met Hy's Law criteria (ALT>3 times ULN or AST>3 times ULN,
associated with total bilirubin >2 times ULN and serum alkaline
phosphatase <2 times ULN). 10 (2.7%) patients had liver function
test results that the investigator deemed clinically significant; 5
(1.4%) patients discontinued due to these adverse events, and all
resolved or were resolving after discontinuation.
[0664] The extended release 7.5 mg OC/325 mg APAP tablets that were
provided to the subjects who participated in this study, delivered
effective pain management. Several measures of pain control and
relief were demonstrated in subjects with either OA or CLBP. Scores
for (i) worst pain in the last 24 hours, (ii) least pain in the
last 24 hours, (iii) average pain in the last 24 hours, and (iv)
current pain all decreased from baseline to the end of treatment,
by 47%, 57%, 52%, and 60% (mean score change), respectively.
Further, the greatest improvement occurred at Day 36. FIG. 101
presents the brief pain inventory (changes in pain intensity from
baseline to end of treatment). Substantial decreases in pain
intensity (worst pain, average pain, and current pain) were
observed early in treatment and continued throughout the study. In
addition, patients' mean score for pain interference questions
(0=no interference; 10=completely interferes) decreased from 5.4 at
baseline to 2.2 at end of treatment (change from baseline, -3.2;
P<0.0001).
[0665] The percent of pain relief also increased steadily from
baseline through Day 36 (mean improvement of 55%). Pain-related
quality of life, as measured by the modified Brief Pain Inventory
short form ("mBPI-sf") pain interference score, continually
improved at each visit. FIGS. 102-105 present the changes from
baseline on domains of the WOMAC (pain, stiffness, physical
function, and total) in patients with osteoarthritis. Statistically
significant improvements from baseline to end of treatment were
seen across all domains of the WOMAC for patients with
osteoarthritis. In addition, statistically significant improvements
in function/disability from baseline to end of treatment were
reported by patients with chronic low back pain; RMDQ scores
improved from 11.0 at baseline to 6.1 at endpoint, a reduction of
4.9 points (P<0.001). The WOMAC pain scores and RMDQ scores both
improved from baseline to end of treatment, by 46% (mean total
score, OA) and 45% (mean score, CLBP), respectively.
[0666] Moreover, the 7.5 mg OC/325 mg APAP tablet used in this
study was an immediate release/extended release, opioid/nonopioid
combination product using gastric retentive technology that
demonstrated a safety profile consistent with expectations for a
low dose opioid/APAP combination product. This study further
established that the safety profile of extended dosing (up to 35
days) of the 7.5 mg OC/325 mg APAP tablet and suggests that the 7.5
mg OC/325 mg APAP tablet effectively controls pain management in
patients with OA or CLBP. Overall, no apparent clinically
significant treatment-related trends were observed in most clinical
laboratory test results, vital signs, pulse oximetry measurements,
or physical examination findings. All changes in hematology,
chemistry, urinalysis, vital signs, and oxygen saturation that were
outside of the defined reference range(s) were not clinically
significant according to the investigator. 10 (2.7%) patients had
liver function test values assessed as clinically significant,
although none met Hy's Law criteria. The safety/tolerability
profile of ER OC/APAP was consistent with expectations for an
opioid/APAP combination product. The most frequently reported
adverse events were nausea, vomiting, dizziness, somnolence, and
constipation. Statistically significant analgesia and improvements
in function were observed in patients with osteoarthritis and
chronic low back pain, as measured by BPI, WOMAC, and RMDQ. The
safety, tolerability, and effectiveness findings in this study
support the administration of the 7.5 mg OC/325 mg APAP tablet
disclosed herein every 12 hours to patients for the management of
moderate to severe acute pain.
Example 14
Partial Areas Under the Curve for Oxycodone and Acetaminophen
[0667] Partial AUCs were calculated for a bilayer extended release
tablet disclosed herein containing acetaminophen and oxycodone, and
an immediate release acetaminophen and oxycodone tablet.
Specifically, Partial AUCs were calculated for the acetaminophen
and oxycodone tablets of (1) Treatment B of Example 10, (2)
Treatment C of Example 9, and (3) Treatment D of Example 10. These
results are summarized in Tables 43-46.
TABLE-US-00057 TABLE 43 Mean (SD) Parameter Estimates for Partial
AUCs for Acetaminophen. AUC.sub.0-1.7 h AUC.sub.1.7-48 h
AUC.sub.0-t Study (ng h/mL) (ng h/mL) (ng h/mL) Treatment B (Ex.
10) 6029 28435 32644 Treatment C (Ex. 9) 5854 25539 29741
TABLE-US-00058 TABLE 44 Additional Mean (SD) Parameter Estimates
for Partial AUCs for Acetaminophen. AUC.sub.0-12 h AUC.sub.0-12 h
AUC.sub.12-36 h AUC.sub.8-12 h AUC.sub.0-t Study (ng h/mL) (ng
h/mL) (ng h/mL) (ng h/mL) (ng h/mL) Treatment B (Ex. 10) 25912
22615 7978 4401 32644 Treatment C (Ex. 9) 24102 20875 6854 3910
29741
TABLE-US-00059 TABLE 45 Percent of AUC.sub.0-t Acetaminophen
AUC.sub.1-12 h AUC.sub.12-36 h AUC.sub.0-12h (T.sub.max to end of
(end of dosing (dosing dosing interval to last Study interval)
interval) concentration) AUC.sub.8-12 h Treatment B 79% 69% 24% 13%
(Ex. 10) Treatment C 81% 70% 23% 13% (Ex. 9)
TABLE-US-00060 TABLE 46 Mean(SD) Parameter Estimates for Partial
AUCs for Oxycodone. AUC.sub.0-2.8 h AUC.sub.2.8-48 h AUC.sub.0-t
Study (ng h/mL) (ng h/mL) (ng h/mL) Treatment B 28.75 158.49 185.93
(Ex. 10) Treatment C 27.89 164.27 190.66 (Ex. 9)
[0668] The bioequivalence determinations between two tablets of a
pharmaceutical composition described herein, each containing 7.5 mg
oxycodone and 325 mg acetaminophen and an immediate release tablet
comprising 7.5 mg oxycodone and 325 mg acetaminophen can be found
in Tables 47 and 48.
TABLE-US-00061 TABLE 47 Bioequivalence Determination for
Acetaminophen LSM 90% CI Parameter Ratio Lower Upper Ln
(AUC.sub.0-1.7 h) 101.97 82.90 125.43 Ln (AUC.sub.1.7-48 h) 91.15
80.58 103.11 Ln (AUC.sub.0-t) 93.14 82.40 105.28
TABLE-US-00062 TABLE 48 Bioequivalence Determination for Oxycodone
LSM 90% CI Parameter Ratio Lower Upper Ln (AUC.sub.0-2.8 h) 99.04
87.83 111.68 Ln (AUC.sub.2.8-48 h) 103.21 92.57 115.06 Ln
(AUC.sub.0-t) 102.19 92.34 113.09
[0669] The results demonstrate that the plasma concentrations of
both oxycodone and acetaminophen rose rapidly with no lag time for
a pharmaceutical composition of the present invention and an
immediate release tablet comprising 7.5 mg oxycodone and 325 mg
acetaminophen. See FIG. 29. Further, 30 minutes after
administration of a dose of a pharmaceutical composition of the
present invention (i.e., 2 tablets of 7.5 oxycodone/325
acetaminophen), oxycodone levels were within the therapeutic range
(>5 ng/mL). Thus, an analgesic effect will be seen in opioid
naive patients. In addition, a pharmaceutical composition of the
present invention was able to maintain oxycodone levels above 5
ng/mL for up to 12 hours after dosing, suggesting that the
analgesic effect may extend to the next dosing cycle.
[0670] Concentrations of acetaminophen resulting from a dose of a
pharmaceutical composition of the present invention (i.e., 2
tablets of 7.5 oxycodone/325 acetaminophen), decreased to less than
900 ng/mL (>17% of Cmax) by 12 hours after administration. This
decreased concentration of acetaminophen at the end of the dosing
cycle allows for sufficient acetaminophen or "APAP time off"
between doses.
[0671] Oxycodone and acetaminophen levels from a pharmaceutical
composition of the present invention (i.e., 2 tablets of 7.5
oxycodone/325 acetaminophen) declined at a similar rate to an
immediate release tablet comprising 7.5 mg oxycodone and 325 mg
acetaminophen, with a terminal elimination half-life of
approximately 4 to 5 hours.
Example 15
Partial Areas Under the Curve for Oxycodone and Acetaminophen
Administered with Food
[0672] Partial AUCs were calculated for a bilayer extended release
tablet disclosed herein containing acetaminophen and oxycodone, and
an immediate release acetaminophen and oxycodone tablet.
Specifically, Partial AUCs were calculated for the acetaminophen
and oxycodone tablets of (1) Treatment A of Example 4, (2)
Treatment A of Example 6 (one tablet), and (3) Treatment C of
Example 4. These results are summarized in Tables 49-50.
TABLE-US-00063 TABLE 49 Mean (SD) Parameter Estimates for Partial
AUCs for Acetaminophen. AUC.sub.0-3.2 h AUC.sub.3.2-48 h
AUC.sub.0-t Study (ng h/mL) (ng h/mL) (ng h/mL) Treatment A (Ex. 4)
8042 23810 30245 Treatment A (Ex. 6) 9145 23319 31478 (one
tablet)
TABLE-US-00064 TABLE 50 Mean (SD) Parameter Estimates for Partial
AUCs for Oxycodone. AUC.sub.0-4.3 h AUC.sub.4.3-48 h AUC.sub.0-t
Study (ng h/mL) (ng h/mL) (ng h/mL) Treatment A (Ex. 4) 48.62
152.57 199.43 (15.99) (49.86) (59.47) Treatment A (Ex. 6) 53.29
167.50 219.20 (one tablet) (17.12) (51.83) (55.99)
[0673] The bioequivalence determinations between the pharmaceutical
composition described herein, containing 15 mg oxycodone and 650 mg
acetaminophen and an immediate release product comprising 15 mg
oxycodone and 650 mg acetaminophen can be found in Tables 51 and
52.
TABLE-US-00065 TABLE 51 Bioequivalence Determination for
Acetaminophen LSM 90% CI Parameter Ratio Lower Upper
Ln(AUC.sub.0-3.2 h) 114.46 96.21 136.16 Ln (AUC.sub.3.2-48 h) 94.62
83.31 107.47 Ln (AUC.sub.0-t) 101.32 90.00 114.07
TABLE-US-00066 TABLE 52 Bioequivalence Determination for Oxycodone
LSM 90% CI Parameter Ratio Lower Upper Ln (AUC.sub.0-4.3 h) 109.87
94.98 127.08 Ln (AUC.sub.4.3-48 h) 109.75 94.48 127.48 Ln
(AUC.sub.0-t) 110.53 97.39 125.44
[0674] Exposure to oxycodone and acetaminophen was comparable
between Treatment A of Example 4 and Treatment A of Example 6 (one
tablet). Thus, these results indicate that the release of oxycodone
and acetaminophen is consistent across studies. Plasma
concentration-time profiles are presented in FIGS. 30A and 30B.
[0675] The initial exposure to oxycodone (AUC.sub.0-4.3h) was
slightly outside the bioequivalence parameters established by the
FDA (upper 90% CI 127%). The initial exposure to acetaminophen
(AUC.sub.0-3.2h) was outside of the FDA's bioequivalence parameters
(upper 90% CI 136%).
[0676] The extended (sustained) exposure to oxycodone
(AUC.sub.4.3-48h) was slightly outside the FDA's limit for
bioequivalence (upper 90% CI 127%). However, the extended exposure
to acetaminophen (AUC.sub.3.2-48h) and total exposure (AUC.sub.0-t)
for both oxycodone and acetaminophen was equivalent between
studies.
Example 16
Mechanical Crushing into Powder Form
[0677] Drug abusers often tamper with extended release
opioid-containing formulations by crushing the dosage form. This
process generally serves several functions, including destroying
the extended release properties of the dosage form and enabling the
dosage form to be processed for unintended methods of
administration, such as snorting or intravenous injection.
Accordingly, comparative tamper resistance experiments were
performed on an extended release tablet dosage form of the
pharmaceutical composition of the present invention containing 7.5
mg oxycodone HCl and 325 mg acetaminophen (see Chart 1) (the
"product") and a commercially available immediate-release tablet
containing 7.5 mg oxycodone/325 mg acetaminophen (the
"comparator").
[0678] The product and comparator tablets were subjected to
standard mechanical crushing by the following means: a hammer, a
pill crusher, a mortar and pestle, a knife, two spoons, a utility
knife, a blender, a coffee mill, and a coffee grinder. The success
or failure of the particle size reduction was then visually
assessed. In some cases, a sieving analysis was also utilized to
quantitatively measure if significant particle size reduction
occurred. Generally, drug abusers desire to crush pharmaceutical
formulations into a fine powder, as this form is convenient for
processing the tablet into a snortable or injectable form.
[0679] The results demonstrated that in most instances, the
comparator was easily broken down into smaller pieces by each of
the mechanical means listed above. Accordingly, in most instances,
the comparator offered little tamper resistance as it could easily
be mechanically crushed into a suitable powder. In contrast, the
physical properties of the product tablet prevented the product
tablet from being crushed into a fine powder. Indeed, in relation
to the comparator, the product tablet was more difficult to break
down using the methods listed above. Specifically, all of the
mechanical methods described above were ineffective at producing a
suitable powder from the product tablets except grinding in a
mortar and pestle. Consequently, the product tablets offer improved
protection from the mechanical crushing methods employed by drug
abusers.
Example 17
Abuse Resistance Properties of Product Powders Produced by Grinding
Using a Mortar and Pestle
[0680] An in vitro dissolution test with human abuse liability
("HAL") predictions was conducted to determine the cumulative
amount of drug released from intact and crushed tablets of the
extended release pharmaceutical compositions disclosed herein and a
commercially-available immediate release oxycodone and
acetaminophen tablet.
[0681] Comparator tablets (the "comparator") containing a total of
7.5 mg of oxycodone HCl and a total of 325 mg acetaminophen were
obtained. Six comparator tablets were ground with a mortar and
pestle and placed into capsules, while six tablets were used as is
(i.e., kept intact, but placed into capsules). Dissolution profiles
for the intact and crushed tablets were determined in a USP type II
apparatus. Six intact tablets and six crushed tablets were weighed,
placed in a sinker, and dropped into an equilibrated dissolution
bath vessel containing 900 mL of (helium sparged) 0.1 N HCl heated
to 37.degree. C..+-.0.5.degree. C. The mixture was stirred at
100.+-.4 rpm, and the temperature was maintained at 37.degree.
C..+-.0.5.degree. C. for 12 hr. The bath vessel was covered with a
low evaporation vessel cover. Samples (5 mL) were removed at 5 min,
10 min, 20 min, 30 min, and 60 min. Each sample was filtered
through a 0.45 .mu.m filter and analyzed by HPLC using standard
procedures. The release profile of oxycodone HCl from intact and
crushed comparator is shown in FIG. 31.
[0682] Bilayer formulations described herein were prepared, each
containing a total of 7.5 mg of oxycodone HCl, a total of 325 mg of
acetaminophen, and an extended release polymer. Six product tablets
(as defined in Example 16) were ground with a mortar and pestle and
placed into capsules, while twelve product tablets were used as is.
The same dissolution method as described for the intact and crushed
comparator above was used to obtain release profiles for intact and
crushed product tablets. However, six of the intact product tablets
(labeled as "Intact") were sampled (5 mL) at 0.25 hr, 0.5 hr, 1 hr,
2 hr, 4 hr, 6 hr, 8 hr, and 12 hr. The release profiles of
acetaminophen and oxycodone HCl from the intact and crushed product
tablets are shown in FIGS. 32A and 32B (for acetaminophen) and 33A
and 33B (for oxycodone). In these figures, "intact" refers to the
intact product tablets sampled at 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4
hr, 6 hr, 8 hr, and 12 hr. "HAL_Intact" refers to the intact
product tablets sampled at the same time intervals as the crushed
tablets, namely, 5 min, 10 min, 20 min, 30 min, 1 hr, 2 hr, 4 hr, 6
hr, 8 hr, 12 hr.
[0683] These results show that for release of oxycodone HCl from
the comparator tablets, there is no substantial difference in the
release profiles for crushed and intact tablets for abuse purposes.
In each case, almost all of the oxycodone HCl was released in as
little as ten minutes. In stark contrast, there are substantial
differences in the release profiles for crushed and intact product
tablets. The intact product tablets surprisingly exhibited a higher
release rate of both active ingredients than the crushed product
tablets in the first hour. This suggests that upon grinding the
product tablets, the active ingredients in the immediate release
portion are incorporated into the extended release portion, and the
product tablet loses its immediate release characteristics. This
feature may effectively negate a drug abuser's purpose for crushing
the product tablet in the first place--to obtain an early onset of
analgesia.
[0684] Predicted pharmacokinetic parameters were obtained for these
in vitro release profiles for the crushed and intact products and
comparator tablets by using in vitro in vivo correlation ("IVIVC")
technique. These results, which are summarized in Table 53,
demonstrate that the abuse quotients for the crushed and intact
comparator tablets are orders of magnitude higher than the abuse
quotients for the crushed and intact product tablets. This is
consistent with the experimentally determined pharmacokinetic
parameters from Example 10.
TABLE-US-00067 TABLE 53 Predicted pharmacokinetic parameters and
abuse quotient for intact and crushed product and comparator
tablets. Abuse Quotient Product C.sub.max (ng/mL) T.sub.max (hr)
(ng/mL hr) Predicted Comparator (intact) 32.5 0.16 203.1 Comparator
(crushed) 30.8 0.17 181.2 Product (intact) 17.5 6 2.9 Product
(crushed) 20.6 4 5.2 Experimental - see Example 10 Comparator
(intact) 41.6 0.7 59.4 Product (intact) 16.4 3.2 5.1
Example 18
Preconditioning the Tablets by Crisping
[0685] Drug abusers often precondition the tablet by a process
known as crisping. This procedure is intended to remove some of the
tablet fillers, making the drug easier to crush and insufflate or
inject. Accordingly, an experiment was performed to determine a
drug abuser's ability to crisp a tablet dosage form of the
pharmaceutical composition of the present invention containing 7.5
mg oxycodone HCl and 325 mg acetaminophen (see Chart 1) (the
"product") as compared to a commercially available
immediate-release tablet containing 7.5 mg oxycodone/325 mg
acetaminophen (the "comparator").
[0686] First, the product and comparator tablet were crushed into a
powder and placed in a spoon. The spoon was then heated from
underneath with an open flame. Once the powder began to caramelize
and smoke, the heat was removed and the powder was mixed using a
metal spatula. The spoon was again heated until the powder began to
caramelize further. The heat was once again and removed, and the
powder was allowed to cool. The resulting powders were then removed
from the spoon and placed in a mortar and pestle for subsequent
crushing. The comparator tablet resulted in a powder that could be
easily crushed into a fine powder. Unlike the comparator tablet,
the product tablet resulted in a sticky composition, rendering the
product tablet unsuitable for grinding into a fine powder after the
crisping process.
Example 19
Separation Studies
[0687] To determine the ease at which the immediate release (IR)
and extended release (ER) layers of a bilayer form of the
pharmaceutical composition disclosed herein could be tampered with,
several attempts were made at separating the immediate release (IR)
and extended release (ER) layers of the product (as defined in
Example 18). Initially, a tablet dosage form of the pharmaceutical
composition of the present invention was positioned with the
inscribed side facing up and cut completely through vertically.
Upon slicing the tablet, observations revealed no visual
distinction between the IR and ER layers. The tablet was then
re-oriented and sliced from several additional angles. However, no
demarcation line was observed between the IR and ER layers.
Consequently, a drug abuser could not visually distinguish the IR
and ER layers of the pharmaceutical composition disclosed herein by
simply cutting the dosage form.
Example 20
Injectability Studies
[0688] An injectability study was conducted to determine the extent
to which crushed and dissolved tablets of the pharmaceutical
composition disclosed herein containing 7.5 mg oxycodone/325 mg
acetaminophen (the "product") could be drawn into a syringe for
intravenous administration as compared to a commercially available
immediate-release tablet containing 7.5 mg oxycodone/325 mg
acetaminophen that had been crushed and dissolved (the
"comparator"). Intravenous administration is a common practice used
by drug abusers as a means to potentiate their drugs by
administering the drug as one large bolus instead of a steady
release over time. Two measurable entities were evaluated: the
amount of useable fluid that was harvested through the process and
the concentration of oxycodone in these aliquots. This study
employed a standard 1 mL insulin syringe equipped with 22-, 26-,
and 30-gauge needles, which are the typical sizes of needles used
by intravenous drug users.
[0689] An intact product and comparator tablet were each ground in
a mortar and pestle to yield a fine powder. The powder was then
placed onto a tablespoon secured to a laboratory ring stand. 3 mL
of deionized water was added to the spoon and was mixed into a
slurry in an attempt to dissolve the active ingredient. To enhance
solubility of the drug, a butane lighter was used to uniformly heat
the bottom of the spoon. When the solution began to boil slightly,
heat was removed and any liquid lost was replenished. A traditional
insulin syringe (1 mL) with a makeshift cotton ball filter and the
various gauge needles was used to extract the resulting liquid into
the syringe.
[0690] Three types of cotton filters were evaluated for use in this
procedure. The first filter was a small cotton plug placed between
the needle hub and barrel of the syringe. This filter clogged for
all three gauges when attempts were made to draw liquid into the
syringe. The second filter was formed by inserting the tip of the
syringe needle into the end of a Q-tip. This second filter also
prevented an appreciable amount of fluid to be drawn into the
syringe. The third filter was a small piece of cotton attached to
the end of the needle. The third filter was chosen for further
study because it was the only filter evaluated in which liquid
could be drawn into the syringe for all three gauges without
clogging the filter. The drawn liquid was collected, measured and
quantified by LC/MS/MS analysis.
[0691] When water was mixed with the ground product tablet, the
solid did not completely dissolve upon heating. Instead, a pasty
material was produced that did not readily disperse when mixed. The
product required almost constant mixing of the crushed powder and
water with constant heating to produce a removable liquid. It was
difficult to generate a homogeneous mixture of liquid that could be
drawn into a syringe because the combined volume of the crushed
product tablet and the 3 mL of water essentially filled the spoon
to capacity. Additionally, with heating, it was necessary to
replenish the evaporated water to maintain a constant slurry level
in the spoon. Liquid samples were drawn from the bottom of the
spoon with a 1 mL syringe with the cotton plug on the tip. This
study demonstrated that only about 1 mL of liquid could
consistently be drawn into the syringe, independent of needle size.
The resulting liquid in the syringe was murky and not transparent
due to particulate matter.
[0692] In contrast, a large portion of the comparator readily
dissolved when mixed and heated in the tablespoon. The resulting
liquid in the syringe therefore contained much less particulate
matter than the liquid resulting from the product tablet.
[0693] These results indicate that injection is not a preferred
form of drug diversion for the product tablets. When adding water
to the ground tablets, the user may recover only a small portion of
that liquid for use in a syringe. The product tablet tended to
produce a semi-solid paste that interfered with liquid recovery
through the syringe. The overall results indicate a recovery of
less than 20% of the oxycodone in the product tablet.
Example 21
Snorting Studies
[0694] Another method of tampering and diversion is to grind a
tablet into a fine powder and insufflate (snort) the powder. The
inhaled powder is deposited inside the nasal passage, and the
oxycodone is absorbed through the mucous membranes of the nasal
passage. In order for the procedure to work efficiently, the powder
must deposit as a thin layer onto the nasal tissue in the sinus
cavity. A study was performed to estimate the effectiveness of this
process using the pharmaceutical composition disclosed herein
containing 7.5 mg oxycodone/325 mg acetaminophen (the "product")
and a commercially available immediate-release tablet containing
7.5 mg oxycodone/325 mg acetaminophen (the "comparator").
[0695] Product tablet and a comparator tablet were ground in a
mortar and pestle. 1 mL of water was added to each ground tablet,
and the resulting combination was mixed in an attempt to produce a
thin slurry, which mimics the interface between the nasal passage
and the absorptive tissue. The product tablet formed a paste that
tended to clump. The comparator produced a more fluid consistency.
Consequently, the comparator produced a more effective coating for
absorption of insufflated oxycodone in the nasal cavity than the
product disclosed herein.
Example 22
Dose Dumping Studies
[0696] Dose dumping is the process of releasing the active
ingredient(s) of an extended release pharmaceutical formulation in
a short period of time in a manner in which the entire dosage, or a
significant portion of the dosage, becomes available for absorption
in the body. This is often achieved by ingesting tablets along with
alcoholic beverages to enhance drug delivery. The alcohol serves as
a means to act on either the coating of a tablet to help release
the active ingredients or to promote greater absorption within the
body. This method is employed by drug abusers as an attempt to
potentiate analgesic drugs. Release of elevated quantities of drug
can lead to increased euphoric effects but can also cause adverse
effects, some of which may be fatal.
[0697] Two dissolution experiments were performed in a dose dumping
study. The dissolutions were designed to examine the differences
between intact pharmaceutical compositions disclosed herein
containing 7.5 mg oxycodone/325 mg acetaminophen (the "product")
and a commercially available immediate-release tablet containing
7.5 mg oxycodone/325 mg acetaminophen (the "comparator") when
exposed to simulated gastric fluid dissolution media ("SGF"). The
first dissolution was performed in 75 mL of SGF in the absence of
vodka. The second dissolution was performed in 75 mL of a 50:50
mixture of SGF and 80-proof vodka. This was designed to measure the
extent that the product and comparator may be abused by the
simultaneous intake of alcohol. Both dissolutions were performed at
room temperature and were mixed on a stir plate. Aliquots were
removed at 0.25, 0.50, 1, 2 and 4 hours for quantification by
LC/MS/MS, a summary of which is contained in Table 54 below.
TABLE-US-00068 TABLE 54 Mean percent recovery of oxycodone in (i)
simulated gastrointestinal fluid and (ii) a solution containing 50%
simulated gastric fluid and 50% 80-proof vodka. Mean Percent
Recovery at time = t Fluid Intact Tablet 0.25 hr 0.5 hr 1 hr 2 hr 4
hr SGF Product 15% 30% 43% 57% 80% SGF Comparator 104% 102% 105%
102% 100% SGF:EtOH Product 12% 23% 35% 46% 62% SGF:EtOH Comparator
101% 101% 103% 100% 102%
[0698] At the end of the four hour dissolution, the product tablets
were still visible but had lost their outer coating in SGF both in
the presence and absence of vodka. Addition of ethanol to the SGF
produced a slight decrease in the dissolution rate of the product
tablet. Comparator tablets were dissolved in SGF both in the
presence and absence of vodka after five minutes. Consequently, the
product tablets were resistant to dose dumping when compared to the
comparator tablets.
Example 23
Varying Polyox Grades Comprising 25% by Weight of the Extended
Release Portion of Bilayer Formulations
[0699] Single layer tablet formulations containing only the
extended release portion were prepared, each tablet containing a
total of 9 mg of oxycodone HCl and a total of 250 mg of
acetaminophen. Since these tablets contained only the extended
release portion, they contained 50% of the total acetaminophen for
the bilayer tablet and 60% of the total oxycodone HCl for the
bilayer tablet. In a first formulation, POLYOX.RTM. 205 was
employed as the extended release component in an amount of 25% by
weight of the ER portion, and therefore, the tablet weight. In a
second formulation, POLYOX.RTM. 1105 was employed as the extended
release component in an amount of 25% by weight of the tablet of ER
portion. In a third formulation, POLYOX.RTM. N-60K was employed as
the extended release component in an amount of 25% by weight of the
tablet or ER portion.
[0700] Dissolution profiles for the three above-described
compositions were determined in USP Type II apparatus. Six tablets
of each composition were weighed, placed in a sinker, and dropped
into an equilibrated dissolution bath vessel containing 900 mL of
(helium sparged) 0.1 N HCl heated to 37.degree. C..+-.0.5.degree.
C. The mixture was stirred at 150.+-.6 rpm, and the temperature was
maintained at 37.degree. C..+-.0.5.degree. C. through 12 hr. The
bath vessel was covered with a low evaporation vessel cover.
Samples (5 mL) were removed at 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 hr,
6, hr, 8 hr, and 12 hr. The final time point for the Polyox 205 was
17 hrs; the final time point for the Polyox 1105 was 15 hrs; and
the final time point for the Polyox N60k was 18 hrs and 40 minutes.
Each sample was filtered through a 0.45 .mu.m filter and analyzed
by HPLC using standard procedures.
[0701] The cumulative release profiles of acetaminophen and
oxycodone from these compositions are shown in FIGS. 34 and 35,
respectively. This data represents dissolution for the extended
release portion with the immediate release data theoretically
added. These figures demonstrate that as the average molecular
weight of the POLYOX.RTM. extended release component increases, the
rate of dissolution at each time point decreases. For example, the
formulations containing POLYOX.RTM. 205, 1105, and N-60K had
released about 59%, about 56%, and about 55% acetaminophen after 15
minutes, respectively; about 63%, about 59%, and about 57%
acetaminophen after 30 minutes, respectively; about 69%, about 64%,
and about 61% acetaminophen after 1 hr, respectively; about 78%,
about 73%, and about 67% acetaminophen after 2 hr, respectively;
about 91%, about 87%, and about 76% acetaminophen after 4 hr,
respectively; about 97%, about 95%, and about 84% acetaminophen
after 6 hr, respectively; and about 98%, about 97%, and about 90%
acetaminophen after 8 hr, respectively.
[0702] The same general trend of a decreased release rate with a
higher molecular weight POLYOX.RTM. grade was also observed for the
oxycodone. For example, the formulations containing POLYOX.RTM.
205, 1105, and N-60K had released about 53%, about 50%, and about
48% oxycodone after 15 minutes, respectively; about 60%, about 56%,
and about 53% oxycodone after 30 minutes, respectively; about 68%,
about 63%, and about 59% oxycodone after 1 hr, respectively; about
80%, about 75%, and about 67% oxycodone after 2 hr, respectively;
about 94%, about 91%, and about 80% oxycodone after 4 hr,
respectively; about 100%, about 98%, and about 89% oxycodone after
6 hr, respectively; and about 100%, about 99%, and about 95%
oxycodone after 8 hr, respectively.
Example 24
Varying Polyox Grades Comprising 45% by Weight of the Extended
Release Portion of Bilayer Formulations
[0703] Single layer formulations containing only the extended
release portion described herein were prepared, each tablet
containing a total of 9 mg of oxycodone HCl and a total of 250 mg
of acetaminophen. Since these tablets contained only the extended
release portion, they contained 50% of the total acetaminophen for
a bilayer tablet and 60% of the total oxycodone HCl for a bilayer
tablet. In a first formulation, POLYOX.RTM. 205 was employed as the
extended release component in an amount of 45% by weight of the
tablet or ER portion. In a second formulation, POLYOX.RTM. 1105 was
employed as the extended release component in an amount of 45% by
weight of the tablet or ER portion. In a third formulation,
POLYOX.RTM. N-60K was employed as the extended release component in
an amount of 45% by weight of the tablet or ER portion. The other
excipients in the extended release portion were microcrystalline
cellulose, spress B825, citric acid anhydrous, EDTA, hydroxypropyl
cellulose, silicon dioxide, and magnesium stearate.
[0704] Dissolution profiles for the three above-described
formulations were determined in USP Type II apparatus. Six tablets
of each formulation were weighed, placed in a sinker, and dropped
into an equilibrated dissolution bath vessel containing 900 mL of
(helium sparged) 0.1 N HCl heated to 37.degree. C..+-.0.5.degree.
C. The mixture was stirred at 150.+-.6 rpm, and the temperature was
maintained at 37.degree. C..+-.0.5.degree. C. through 12 hr. The
bath vessel was covered with a low evaporation vessel cover.
Samples (5 mL) were removed at 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 hr,
6, hr, 8 hr, and 12 hr. The final time point for the Polyox 205 was
17 hours; the final time point for Polyox 1105 was 17.5 hours; and
the final time point for Polyox N60k was 23.5 hours. Each sample
was filtered through a 0.45 .mu.m filter and analyzed by HPLC using
standard procedures.
[0705] The cumulative release profiles of acetaminophen and
oxycodone from these compositions are shown in FIGS. 36 and 37,
respectively. This data represents dissolution for the extended
release portion with the immediate release data theoretically
added. Consistent with the results of Example 23, the rate of
dissolution at each time point decreases as the molecular weight of
POLYOX.RTM. increases. For example, the formulations containing
POLYOX.RTM. 205, 1105, and N-60K had released about 53%, about 53%,
and about 53% acetaminophen after 15 minutes, respectively; about
56%, about 55%, and about 54% acetaminophen after 30 minutes,
respectively; about 61%, about 60%, and about 57% acetaminophen
after 1 hr, respectively; about 70%, about 67%, and about 63%
acetaminophen after 2 hr, respectively; about 85%, about 81%, and
about 71% acetaminophen after 4 hr, respectively; about 95%, about
90%, and about 79% acetaminophen after 6 hr, respectively; about
99%, about 95%, and about 85% acetaminophen after 8 hr,
respectively; and about 99%, about 96% and about 93% acetaminophen
after 12 hr.
[0706] The formulations containing POLYOX.RTM. 205, 1105, and N-60K
also released about 47%, about 47%, and about 46% oxycodone after
15 minutes, respectively; about 51%, about 50%, and about 49% after
30 minutes, respectively; about 59%, about 56%, and about 53%
oxycodone after 1 hr, respectively; about 70%, about 67%, and about
62% oxycodone after 2 hr, respectively; about 88%, about 83%, and
about 74% oxycodone after 4 hr, respectively; about 99%, about 93%,
and about 83% oxycodone after 6 hr, respectively; and about 100%,
about 97%, and about 90% oxycodone after 8 hr, respectively.
Example 25
Varying the Concentrations of a Specific Polyox Grade in the
Extended Release Portion of Bilayer Formulations
[0707] The data from Examples 23 and 24 indicate that an increase
in the amount of POLYOX.RTM. in the pharmaceutical composition
retards the release of oxycodone and acetaminophen from the
pharmaceutical composition. To confirm this observation, single
layer extended release formulations described herein were prepared,
each containing a total of 9 mg of oxycodone HCl and a total of 250
mg of acetaminophen. Since these tablets contained only the
extended release portion, they contained 50% of the total
acetaminophen for the bilayer tablet and 60% of the total oxycodone
for the bilayer tablet. In a first formulation, POLYOX.RTM. 1105
was employed as the extended release component in an amount of 25%
by weight of the tablet or ER portion. In a second formulation,
POLYOX.TM. 1105 was employed as the extended release component in
an amount of 35% by weight of the tablet or ER portion. In a third
formulation, POLYOX.TM. 1105 was employed as the extended release
component in an amount of 45% by weight of the tablet or ER
portion. In a fourth formulation, POLYOX.RTM. 1105 was employed as
the extended release component in an amount of 55% by weight of the
tablet or ER portion. The amount of the microcrystalline cellulose
in the four formulations was adjusted to account for the differing
amounts of POLYOX.RTM. 1105 in each formulation. The other
excipients in the extended release portion were B825, citric acid
anhydrous, EDTA, hydroxypropyl cellulose, silicon dioxide, and
magnesium stearate. However, the percentages for all the other
excipients remained the same for each formulation, and were
consistent with the percentages used in Example 24.
[0708] Dissolution profiles for the above-described formulations
were determined in USP Type II apparatus. Six tablets of each
formulation were weighed, placed in a sinker, and dropped into an
equilibrated dissolution bath vessel containing 900 mL of (helium
sparged) 0.1 N HCl heated to 37.degree. C..+-.0.5.degree. C. The
mixture was stirred at 150.+-.6 rpm, and the temperature was
maintained at 37.degree. C..+-.0.5.degree. C. through 12 hr. The
bath vessel was covered with a low evaporation vessel cover.
Samples (5 mL) were removed at 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 hr,
6, hr, 8 hr, and 12 hr. The final time point for the 25%, 35%, 45%,
and 55% formulations was 15 hr, 15 hr, 17.5 hr, and 17.5 hr,
respectively. Each sample was filtered through a 0.45 .mu.m filter
and analyzed by HPLC using standard procedures.
[0709] The cumulative release profiles of acetaminophen and
oxycodone from these compositions are shown in FIGS. 38 and 39,
respectively. These profiles confirm that as the amount of
POLYOX.RTM. 1105 used in the pharmaceutical formulations increase,
the release rate of the acetaminophen and oxycodone generally
decreases. For example, the formulations containing 25%, 45%, and
55% POLYOX.RTM. 1105 had released about 56%, about 53%, and about
53% acetaminophen after 15 minutes, respectively; about 59%, about
56%, about 55%, and about 55% acetaminophen after 30 minutes,
respectively; about 64%, about 61%, about 60%, and about 59%
acetaminophen after 1 hr, respectively; about 73%, about 70%, about
67%, and about 66% acetaminophen after 2 hr, respectively; about
87%, about 84%, about 81%, and about 79% acetaminophen after 4 hr,
respectively; about 95%, about 93%, about 90%, and about 89%
acetaminophen after 6 hr, respectively; about 97%, about 97%, about
95%, and about 95% acetaminophen after 8 hr, respectively; and
about 97%, about 97%, about 96%, and about 98% acetaminophen after
12 hr, respectively.
[0710] Similar trends were observed for the cumulative release of
oxycodone. However, there was no observable difference in the
release of oxycodone from the formulations containing 45% and 55%
POLYOX.RTM. 1105. For example, the formulations containing 25%,
45%, and 55% POLYOX.RTM. 1105 had released about 50%, about 47%,
and about 45% oxycodone after 15 minutes, respectively; about 56%,
about 51%, about 50%, and about 50% oxycodone after 30 minutes,
respectively; about 63%, about 58%, about 56%, and about 56%
oxycodone after 1 hr, respectively; about 75%, about 70%, about
67%, and about 66% oxycodone after 2 hr, respectively; about 91%,
about 87%, about 83%, and about 82% oxycodone after 4 hr,
respectively; about 98%, about 96%, about 93%, and about 93%
oxycodone after 6 hr, respectively; about 99%, about 99%, about
97%, and about 98% oxycodone after 8 hr, respectively; and about
99%, about 100%, about 97%, and about 100% oxycodone after 12 hr,
respectively.
Example 26
In vitro Dissolution of Controlled-Release Bilayer Tablets
Containing 7.5 mg Oxycodone and 325 mg Acetaminophen Performed at a
100 rpm Paddle Speed
[0711] Three batches of bilayer formulations described herein were
prepared, each containing a total of 7.5 mg of oxycodone HCl and a
total of 325 mg of acetaminophen. 50% of the acetaminophen was
contained in the immediate release portion, and the other 50% was
contained in the ER layer. 25% of the oxycodone HCl was contained
in the immediate release portion of the formulation, and the other
75% was contained in the ER layer. POLYOX.TM. 1105 was employed as
the extended release component in an amount of 45% by weight of the
ER portion.
[0712] Dissolution profiles for the formulations of each batch were
determined in a USP Type II apparatus. Twelve tablets from each
batch were weighed, placed in a sinker, and dropped into an
equilibrated dissolution bath vessel containing 900 mL of (helium
sparged) 0.1 N HCl heated to 37.degree. C..+-.0.5.degree. C. The
mixture was stirred at 100.+-.4 rpm, and the temperature was
maintained at 37.degree. C..+-.0.5.degree. C. for 12 hr. The bath
vessel was covered with a low evaporation vessel cover. Samples (5
mL) were removed at 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 hr, 6, hr, 8 hr,
and 12 hr. Each sample was filtered through a 0.45 .mu.m filter and
analyzed by HPLC using standard procedures.
[0713] The cumulative percent release of acetaminophen and
oxycodone from each batch are described in Table 55.
TABLE-US-00069 TABLE 55 Release rate data of bilayer tablets (7.5
mg oxycodone HCl; 325 mg acetaminophen) using a 100 rpm dissolution
method. Oxycodone HCl Acetaminophen Time Max Mean Max (Hours) Mean
(%) RSD Min (%) (%) (%) RSD Min (%) (%) Batch 1 0.25 31.7 2.1 30.6
32.5 51.8 1.4 50.9 53.1 0.5 37.1 1.3 36.3 37.8 54.3 1.3 53.5 55.6
1.0 45.4 1.0 44.9 46.0 58.6 1.2 57.7 60.1 2.0 58.5 1.3 57.4 59.7
66.0 1.2 64.8 67.7 4.0 78.6 1.7 76.8 80.5 78.5 1.5 77.0 80.6 6.0
92.2 1.8 90.0 94.7 88.0 1.6 86.0 90.3 8.0 99.5 1.8 97.4 102.7 93.8
1.5 91.8 96.3 12.0 101.7 1.4 99.7 104.3 96.1 1.0 94.9 98.2 Batch 2
0.25 31.6 3.5 29.6 34.0 52.1 4.0 48.8 55.8 0.5 37.2 3.2 34.9 39.9
54.5 3.8 51.4 58.3 1.0 45.4 3.3 42.4 48.3 59.1 3.5 56.0 63.1 2.0
58.9 1.7 57.3 61.1 66.4 3.0 63.6 70.0 4.0 79.1 1.5 77.7 81.5 78.7
2.5 75.4 81.8 6.0 93.1 1.3 91.5 95.8 87.7 2.2 84.4 90.7 8.0 100.2
1.2 98.7 102.3 93.5 1.9 90.4 96.2 12.0 102.7 1.3 100.4 104.4 95.6
2.0 92.6 98.4 Batch 3 0.25 30.4 1.6 29.3 31.0 52.2 2.3 49.6 54.2
0.5 35.7 1.6 34.2 36.7 54.6 2.3 52.0 56.6 1.0 43.5 1.8 42.0 45.1
58.6 2.2 56.0 60.8 2.0 56.1 1.9 54.4 58.0 65.5 2.1 63.1 68.0 4.0
75.4 1.8 73.3 77.6 77.3 2.0 74.8 80.0 6.0 88.9 1.7 86.1 91.4 86.5
2.2 83.7 90.1 8.0 97.0 1.5 94.7 99.8 93.0 2.1 90.1 96.8 12.0 100.4
1.1 98.7 102.4 96.5 1.6 93.2 98.3
Example 27
In vitro Dissolution of Controlled-Release Bilayer Tablets
Containing 15 mg Oxycodone and 650 mg Acetaminophen Performed at a
150 rpm Paddle Speed
[0714] Bilayer formulations described herein were prepared, each
containing a total of 15 mg of oxycodone HCl and a total of 650 mg
of acetaminophen. 50% of the acetaminophen was contained in the
immediate release portion, and the other 50% was contained in the
ER layer. 25% of the oxycodone HCl was contained in the immediate
release portion of the formulation, and the other 75% was contained
in the ER layer. POLYOX.TM. 1105 was employed as the extended
release component in an amount of 45% by weight of the ER
portion.
[0715] Dissolution profiles for the formulations were determined in
a USP Type II apparatus. Six tablets were weighed, placed in a
sinker, and dropped into an equilibrated dissolution bath vessel
containing 900 mL of (helium sparged) 0.1 N HCl heated to
37.degree. C..+-.0.55.degree. C. The mixture was stirred at
150.+-.6 rpm, and the temperature was maintained at 37.degree.
C..+-.0.5.degree. C. for 12 hr. The bath vessel was covered with a
low evaporation vessel cover. Samples (5 mL) were removed at 0.25
hr, 0.5 hr, 1 hr, 2 hr, 4 hr, 6, hr, 8 hr, and 12 hr. Each sample
was filtered through a 0.45 .mu.m filter and analyzed by HPLC using
standard procedures.
[0716] The cumulative percent release of acetaminophen and
oxycodone from each batch are described in Table 56.
TABLE-US-00070 TABLE 56 Release rate data of bilayer tablets (15 mg
oxycodone HCl; 325 mg acetaminophen) using a 150 rpm dissolution
method. Time (hr) Oxycodone HCl (%) Acetaminophen (%) 0.25 33.7
54.4 0.50 39.0 56.5 1 47.4 60.6 2 61.4 68.1 4 81.7 81.1 6 95.2 90.8
8 101.2 96.0 12 102.3 97.6
Example 28
Ethanol Release Testing at a 100 rpm Paddle Speed
[0717] The ethanol release studies discussed above in Example 8
were repeated, except that the solutions were stirred at a paddle
speed of 100 rpm and additional aliquots were sampled at 240 min
and 480 min. Tables 57, 58, 59, 60, and 61 present the percent
release of OC and APAP in the presence of 0%, 5%, 10%, 20%, and 40%
ethanol, respectively. FIG. 40 presents dissolution profiles for OC
and FIG. 41 presents dissolution profiles for APAP in the presence
of 0%, 5%, 20%, and 40% ethanol. Like the results at a paddle speed
of 150 rpm, these data reveal that, for both OC and APAP, the
dissolution in 5%, 20%, or 40% ethanol was either comparable or
slower than the dissolution in 0% ethanol, indicating no dose
dumping for this formulation.
TABLE-US-00071 TABLE 57 Percent Release in 0% Ethanol Time OC APAP
(Min) Mean RSD Minimum Maximum Mean RSD Minimum Maximum 15 32.5 3.7
31.5 36.0 52.2 1.6 50.7 53.4 30 37.6 2.5 36.6 39.9 54.6 1.4 53.2
55.7 45 42.1 2.7 40.9 44.8 56.8 1.4 55.3 57.9 60 45.8 2.1 44.6 48.1
58.8 1.4 57.4 59.8 75 49.6 2.3 48.2 52.2 60.8 1.4 59.2 61.8 90 53.1
2.4 51.7 55.8 62.6 1.4 60.9 63.8 105 56.3 2.4 54.8 59.3 64.3 1.4
62.6 65.6 120 59.5 2.5 57.6 63.0 66.0 1.4 64.2 67.3 240 80.3 2.5
77.3 84.9 78.6 1.8 76.3 80.6 480 102.4 1.8 100.5 107.2 95.5 1.6
92.6 97.7
TABLE-US-00072 TABLE 58 Percent Release in 5% Ethanol Time OC APAP
(Min) Mean RSD Minimum Maximum Mean RSD Minimum Maximum 15 31.5 2.5
30.0 32.9 52.6 2.1 51.4 55.1 30 36.8 2.4 35.6 38.5 55.1 2.0 53.8
57.6 45 40.9 2.8 38.9 43.5 57.1 2.0 55.8 59.6 60 44.6 3.7 42.1 48.4
58.9 2.0 57.6 61.4 75 48.0 3.6 46.0 52.6 60.7 1.9 59.4 63.2 90 51.0
3.1 49.3 55.3 62.3 1.9 61.0 64.7 105 54.3 3.2 51.8 58.6 63.9 2.0
62.6 66.4 120 57.1 3.2 54.6 61.7 65.5 1.9 64.1 67.8 240 76.6 3.2
73.8 83.0 77.2 2.1 75.5 80.6 480 99.9 2.7 95.8 106.8 94.4 1.7 92.6
98.1
TABLE-US-00073 TABLE 59 Percent Release in 10% Ethanol Time OC APAP
(Min) Mean RSD Minimum Maximum Mean RSD Minimum Maximum 15 30.3 3.1
28.9 32.1 51.7 1.8 50.1 53.4 30 35.6 3.3 33.7 37.3 54.1 1.9 52.4
55.8 45 39.6 2.6 37.6 40.9 56.0 1.9 54.3 57.8 60 43.1 2.6 41.2 44.7
57.8 1.9 56.1 59.5 75 46.2 2.3 44.1 47.5 59.5 1.8 57.7 61.1 90 49.3
2.1 47.3 50.6 61.1 1.8 59.3 62.8 105 52.2 2.2 50.1 53.6 62.6 1.8
60.9 64.2 120 54.8 2.3 52.8 56.4 64.1 1.8 62.3 65.6 240 73.8 2.2
70.8 76.1 75.5 1.7 73.4 77.4 480 98.4 2.1 94.7 101.1 93.5 1.6 91.0
95.9
TABLE-US-00074 TABLE 60 Percent Release in 20% Ethanol Time OC APAP
(Min) Mean RSD Minimum Maximum Mean RSD Minimum Maximum 15 28.0 6.0
23.9 30.3 50.2 5.1 43.0 53.0 30 33.6 4.5 30.7 35.6 53.4 3.1 49.5
55.9 45 37.9 2.9 35.7 39.6 55.5 2.6 52.6 57.9 60 41.2 3.1 39.2 43.2
57.3 2.3 55.1 59.8 75 44.1 2.9 42.3 46.6 59.0 2.2 57.0 61.4 90 46.5
3.5 42.7 49.1 60.5 2.1 58.6 62.9 105 49.8 2.9 48.0 52.8 61.9 2.1
60.2 64.4 120 52.2 2.8 49.9 54.8 63.3 2.0 61.7 65.9 240 72.2 2.1
69.4 74.7 76.0 1.7 74.1 78.4 480 95.7 2.3 91.7 98.7 91.9 1.7 89.3
94.6
TABLE-US-00075 TABLE 61 Percent Release in 40% Ethanol Time OC APAP
(Min) Mean RSD Minimum Maximum Mean RSD Minimum Maximum 15 11.9
13.9 10.0 15.1 16.7 23.2 12.3 22.9 30 21.1 15.4 17.3 26.2 30.4 22.3
21.7 40.7 45 26.8 11.6 22.4 30.3 38.5 15.3 29.6 44.8 60 30.8 7.0
26.8 34.0 43.1 9.2 35.9 47.1 75 34.2 5.0 31.5 36.8 46.1 5.3 41.1
49.2 90 36.9 3.2 35.1 38.8 48.3 3.3 44.6 50.2 105 39.6 3.3 37.3
41.2 49.8 2.4 47.3 51.3 120 41.9 3.3 39.4 44.2 51.1 2.3 48.3 52.7
240 57.0 1.8 55.7 58.9 60.8 2.0 58.9 63.6 480 80.6 1.6 78.4 83.7
77.2 1.3 75.7 78.7
Example 29
Clinical Evaluation of the Relative Abuse Potential of an Extended
Release Formulation of Oxycodone and Acetaminophen
[0718] A randomized, double-blind, double-dummy, active- and
placebo-controlled study was conducted to assess the relative abuse
potential of a bilayer tablet comprising an immediate release
portion and an extended release portion disclosed herein containing
7.5 mg oxycodone/325 mg acetaminophen (see Chart One) versus an
immediate release oxycodone HCl/acetaminophen tablet in
non-dependent, recreational opioid users. The study consisted of a
screening period, an in-clinic period, and a follow-up period, and
was completed by 55 male and female subjects.
[0719] After the subjects were screened, in-clinic tests were
performed to ensure that the subjects were not physically dependent
on opioids, and that they could discriminate between the effects of
oxycodone versus the placebo. Upon completion, the study
medications were randomly administered as a single oral dose to
each subject, and were as follows:
[0720] Group A: two tablets disclosed herein containing 7.5 mg
oxycodone HCl and 325 mg acetaminophen each plus two placebo
tablets disclosed herein plus eight placebo immediate release
capsules.
[0721] Group B: four tablets disclosed herein containing 7.5 mg
oxycodone HCl and 325 mg acetaminophen each plus eight placebo
immediate release capsules.
[0722] Group C: two immediate release capsules containing 7.5 mg
oxycodone HCl and 325 mg acetaminophen each plus six placebo
immediate release capsules plus four placebo tablets disclosed
herein.
[0723] Group D: four immediate release capsules containing 7.5 mg
oxycodone HCl and 325 mg acetaminophen each plus four placebo
immediate release capsules plus four placebo tablets disclosed
herein.
[0724] Group E: four crushed tablets disclosed herein containing
7.5 mg oxycodone HCl and 325 mg acetaminophen each placed in eight
capsules plus four placebo tablets disclosed herein.
[0725] Group F: four crushed immediate release tablets containing
7.5 mg oxycodone HCl and 325 mg acetaminophen each placed in four
capsules plus four placebo immediate release capsules plus four
placebo tablets disclosed herein.
[0726] Group G: four placebo tablets disclosed herein plus eight
placebo immediate release capsules.
[0727] The study consisted of seven treatment periods, each of
which involved a single treatment of one of the study medications
followed by a wash-out period. All subjects received each of the
seven treatments according to their treatment sequence. Only
subjects who completed all 7 arms of the study are included in the
results set forth below.
[0728] The mean pharmacokinetic parameters for oxycodone are
presented in Table 62, and the oxycodone plasma concentration
versus time profiles are presented in FIG. 42. Further, the mean
pharmacokinetic parameters for acetaminophen are presented in Table
63, and the acetaminophen plasma concentration versus time profiles
are presented in FIG. 43.
TABLE-US-00076 TABLE 62 Mean pharmacokinetic parameters for
oxycodone PK Group Group Group Group Parameters A B C D Group E
Group F AUC0-1 6.30 14.68 16.95 37.51 2.79 25.55 (ng h/mL) AUC0-2
18.18 38.83 43.82 85.04 20.23 67.82 (ng h/mL) AUC0-8 88.05 181.16
129.57 257.73 168.05 224.68 (ng h/mL) AUC0-12 116.43 239.95 148.94
305.18 224.03 266.58 (ng h/mL) AUC0-inf 167.76 339.83 166.35 349.09
286.54 303.84 (ng h/mL) AUC0-t 153.04 313.31 163.72 343.00 276.71
298.80 (ng h/mL) Cmax 14.42 31.36 34.09 66.15 32.22 55.11 (ng/mL)
Tmax (h)a 3.02 2.65 1.25 1.26 3.54 1.49 t1/2 (h) 6.46 6.32 3.92
3.85 4.18 3.83 aMedian
TABLE-US-00077 TABLE 63 Mean pharmacokinetic parameters for
acetaminophen PK Parameters Group A Group B Group C Group D Group E
Group F AUC0-1 2666.81 5650.73 4887.49 9859.41 1042.11 7864.78 (ng
h/mL) AUC0-2 6024.60 12560.98 10489.16 20372.68 4760.07 17585.04
(ng h/mL) AUC0-8 17943.23 37825.20 24864.17 50711.32 27822.46
45789.11 (ng h/mL) AUC0-12 21271.16 44611.06 27236.97 55818.54
34594.15 50463.26 (ng h/mL) AUC0-t 25782.36 53465.93 29082.51
60576.35 41504.81 54797.92 (ng h/mL) AUC0-inf 28522.23 57229.79
30327.22 62661.73 43677.32 56582.84 (ng h/mL) Cmax 4085.26 8735.00
7822.63 15367.59 5451.72 13688.28 (ng/mL) Tmax (h)a 0.94 0.97 0.86
0.78 2.95 1.05 t1/2 (h) 7.03 6.81 4.98 6.08 5.39 5.98 aMedian
[0729] As evidenced in Tables 62 and 63, the 7.5 mg oxycodone HCl
and 325 mg acetaminophen tablets disclosed herein, when crushed,
produced lower AUCs and Cmax values and longer Tmax values than
crushed immediate release 7.5 mg oxycodone HCl and 325 mg
acetaminophen tablets. The subjects also rated the immediate
release 7.5 mg oxycodone HCl and 325 mg acetaminophen tablets
(Group D) higher than the 7.5 mg oxycodone HCl and 325 mg
acetaminophen tablets disclosed herein (Group B) on drug liking,
drug high, and good drug effects. See Table 64; see also FIGS.
44-46.
TABLE-US-00078 TABLE 64 Analysis of Variance for LS Mean Difference
in Emax* - VAS Scores for Drug Liking, Drug High, and Good Drug
Effects Parameter Group B Group D Emax for Drug Liking (points)
26.373 35.558 LS mean (22.755, 29.992) (31.940, 39.177) 95% CI LS
mean difference from -9.19 -- IR-OC/APAP 30/1300 mg (-13.140,
-5.231) 95% CI of difference Unadjusted p-value <.001 Adjusted
p-value <.001 Emax for Drug High (points) 47.889 75.959 LS mean
(41.395, 54.384) (69.464, 82.454) 95% CI LS mean difference from
-28.07 -- IR-OC/APAP 30/1300 mg (-34.924, -21.215) 95% CI of
difference Unadjusted p-value <.001 Adjusted p-value <.001
Emax for Good Drug Effects 55.358 75.317 (points) (47.904, 62.812)
(67.863, 82.772) LS mean 95% CI LS mean difference from -19.96 --
IR-OC/APAP 30/1300 mg (-27.868, -12.050) 95% CI of difference
Unadjusted p-value <.001 Adjusted p-value <.001 *maximum
effect the drug can cause
[0730] Further, it was surprisingly discovered that all the AUC
measurements for oxycodone and acetaminophen were lower for
treatment Group E (four crushed tablets disclosed herein containing
7.5 mg oxycodone HCl and 325 mg acetaminophen placed in eight
capsules for a total dose of 30 mg oxycodone HCl and 1300 mg) than
for treatment Group B (four intact tablets disclosed herein
containing 7.5 mg oxycodone HCl and 325 mg acetaminophen for a
total dose of 30 mg oxycodone HCl and 1300 mg). The Tmax for
oxycodone and for acetaminophen was longer for treatment Group E
than for treatment Group B. In addition, the Cmax of acetaminophen
was lower for treatment Group E than for treatment Group B.
[0731] As shown in Table 65, the results also demonstrated that the
subjects liked the 7.5 mg oxycodone HCl and 325 mg acetaminophen
tablets disclosed herein more when they were intact versus when
they were crushed. Thus, the subjects were more likely to take the
7.5 mg oxycodone HCl and 325 mg acetaminophen tablets disclosed
herein in intact form than in a crushed form. See Table 65.
TABLE-US-00079 TABLE 65* Summary of Take Drug Again Assessment,
ARCI Scores, and Overall Drug Liking Scores Timepoint Group A Group
B Group C Group D Group E Group F Group G Take Drug Again
Assessment ("TDAA") 1 h 59.79 70.98 76.43 80.17 55.34 77.59 52.19 4
h 59.84 74.41 71.50 74.07 68.81 78.07 49.83 8 h 58.69 72.18 69.29
72.68 65.00 73.72 50.12 24 h 58.22 71.34 68.38 71.68 66.45 74.47
49.38 ARCI/AMBG Scores Amphetamine Group Score 0.5 h 11.72 12.96
12.33 13.78 10.45 12.83 10.53 1 h 13.12 16.44 17.03 18.46 12.48
17.72 10.59 2 h 12.46 15.80 14.48 15.90 14.91 16.66 10.60 4 h 10.91
13.84 12.17 13.58 14.00 13.97 9.83 Morphine Benzedrine Group Score
0.5 h 14.90 17.43 16.19 19.44 12.81 16.78 12.41 1 h 17.66 24.62
26.33 29.14 15.64 25.50 12.64 2 h 17.25 23.61 23.03 24.73 20.88
25.55 13.05 4 h 14.28 19.82 17.40 20.10 19.91 20.78 11.48 Global
Assessment Overall Drug Liking 8 h 60.14 72.78 68.36 73.66 67.52
74.07 49.65 24 h 58.38 70.50 68.03 70.83 67.59 73.95 50.90 *Mean
data from the mITT Population as data was unavailable for all 55
subjects.
[0732] Further, the pupils of the subjects who completed the study
were measured prior to administration of any of the study
medications, and prior to each pharmacokinetic sample collection
timepoint for up to 12 hours to determine the effect of the
oxycodone on their pupils. The percentage of the subjects pupils'
constriction is presented in Table 66 and FIG. 47.
TABLE-US-00080 TABLE 66 Summary of Pupillometry Pharmacodynamic
Response from the Pharmacokinetic/Pharmacodynamic Model of
Oxycodone Concentration and Effect on Pupil Diameter (Completers
Population) -- % Constriction Planar 95% Model Standard CI
Treatment Parameter Estimate Error CV % Lower-Upper Group A Imax
(%) 21.87 1.41 6.4 18.99-24.75 Ke0 (1/hr) 1.66 0.38 22.7 0.89-2.42
IC50 5.10 0.61 12.0 3.85-6.35 (ng/mL) Gamma 3.79 1.30 34.3
1.13-6.45 Group B Imax (%) 36.42 1.31 3.6 33.73-39.10 Ke0 (1/hr)
1.79 0.25 14.2 1.27-2.31 IC50 11.36 0.73 6.5 9.87-12.86 (ng/mL)
Gamma 4.21 0.81 19.2 2.56-5.86 Group C Imax (%) 59.78 20.76 34.7
17.38-102.18 Ke0 (1/hr) 1.38 0.12 8.8 1.13-1.63 IC50 17.68 6.51
36.8 4.39-30.97 (ng/mL) Gamma 2.04 0.58 28.5 0.85-3.23 Group D Imax
(%) 47.86 2.65 5.5 42.45-53.28 Ke0 (1/hr) 0.92 0.11 12.0 0.70-1.15
IC50 18.50 1.83 9.9 14.76-22.23 (ng/mL) Gamma 3.72 0.48 12.8
2.74-4.69 Group E Imax (%) 40.76 3.11 7.6 34.41-47.10 Ke0 (1/hr)
1.38 0.20 14.6 0.97-1.80 IC50 11.76 1.09 9.3 9.53-13.99 (ng/mL)
Gamma 2.66 0.51 19.2 1.62-3.70 Group F Imax (%) 48.14 3.44 7.1
41.11-55.16 Ke0 (1/hr) 1.09 0.11 10.2 0.86-1.32 IC50 17.32 1.72 9.9
13.81-20.83 (ng/mL) Gamma 2.91 0.39 13.4 2.12-3.71
Example 30
Single Dose Pharmacokinetic Analysis of an Extended Release
Formulation of Oxycodone and Acetaminophen Administered Under
Fasted Conditions
[0733] An open-label, randomized, single-dose, four-period
crossover study to evaluate the pharmacokinetics, bioavailability
and safety of a bilayer tablet formulation comprising an immediate
release portion and an extended release portion containing 7.5 mg
oxycodone and 325 mg acetaminophen (see selected example from Chart
No. 1) ("Treatment A") with either a commercially-available tablet
containing 15 mg oxycodone ("Treatment B") or a
commercially-available tablet containing 37.5 mg tramadol and 325
mg acetaminophen ("Treatment C") and a commercially-available
immediate release tablet containing 7.5 mg oxycodone and 325 mg
acetaminophen ("Treatment D"), was conducted in healthy subjects in
a fasted state.
[0734] The subjects were randomly assigned to 1 of 4 treatment
sequences: A/D/B/C, B/A/C/D, C/B/D/A, or D/C/A/B. As mentioned
above, Treatments A, B, C, and D were as follows: [0735] Treatment
A: 2 tablets of a bilayer tablet formulation containing 7.5 mg
oxycodone and 325 mg acetaminophen administered orally under fasted
conditions, 1 tablet at a time, at Hour 0 on Day 1 of the period;
[0736] Treatment B: 1 tablet of a commercially-available tablet
containing 15 mg oxycodone administered orally under fasted
conditions at Hour 0 and Hour 6 on Day 1 of the period; [0737]
Treatment C: 1 tablet of a commercially-available tablet containing
37.5 mg tramadol and 325 mg acetaminophen administered orally under
fasted conditions at Hour 0 and Hour 6 on Day 1 of the period; and
[0738] Treatment D: 1 tablet of a commercially-available immediate
release tablet containing 7.5 mg oxycodone and 325 mg acetaminophen
administered orally under fasted conditions at Hour 0 and Hour 6 on
Day 1 of the period.
[0739] Each period started at the check-in and ended at the
check-in of the subsequent period. There was a minimum 7-day
interval between the start of each period. Subjects received their
assigned study drug treatment beginning on Hour 0 of Day 1. In all
4 treatment periods, the subjects fasted for at least 10 hours
before administration of the study drug at Hour 0. Further, for
Treatments B, C, and D, the subjects also fasted for at least 1
hour before the Hour 6 study drug administration.
[0740] During each period, blood samples were collected at
designated times before dosing and up to 36 hours after dosing for
a pharmacokinetic analysis of oxycodone and acetaminophen. The
pharmacokinetic parameters for oxycodone are presented in Table 67,
and the oxycodone plasma concentration versus time profiles are
presented in FIG. 48. Further, the pharmacokinetic parameters for
acetaminophen are presented in Table 68, and the acetaminophen
plasma concentration versus time profiles are presented in FIG.
49.
TABLE-US-00081 TABLE 67 Pharmacokinetic Parameters for Oxycodone by
Treatment (2 hours after second dose) N = 29 AUCt AUCinf F = 7 Cmax
(ng h/ (ng h/ Tmax Tlag Kel t1/2 Treatment M = 22 (ng/mL) mL) mL)
(h) (h) (1/h) (h) A Mean 14.28 167.93 169.38 Median 14.9 166.33
167.26 4 0 0.1579 4.39 % CV 20.6 21.9 21.9 69.3 199.3 15.4 14.5 B
Mean 31.27 334.77 336.46 Median 30.8 338.91 341.14 8 0 0.1793 3.87
% CV 26.1 18.7 18.7 74.8 254.4 8.5 8.5 D Mean 19.42 169.91 171.59
Median 19.4 166.17 167.09 8 0 0.1721 4.03 % CV 23.8 20.2 19.9 61.4
199.3 13.7 12.9
TABLE-US-00082 TABLE 68 Pharmacokinetic Parameters for
Acetaminophen by Treatment N = 29 F = 7 Cmax AUCt AUCinf Tmax Tlag
Kel t1/2 Treatment M = 22 (ng/mL) (ng h/mL) (ng h/mL) (h) (h) (1/h)
(h) A Mean 4653.79 29105.98 30897.99 Median 4420 28862.75 29979.62
0.75 0 0.1364 5.08 % CV 29.2 23.6 23.1 50.2 299.6 30.9 41.6 C Mean
4255.52 29953.73 31051.84 Median 4320 29639 30402.51 2 0 0.1783
3.89 % CV 23.6 21.9 21.6 96.1 160.3 24.8 31.5 D Mean 4387.24
29191.1 30316.61 Median 4430 28834.25 29858.94 0.75 0 0.1694 4.09 %
CV 30.2 23.6 23.6 125.3 373.9 26.6 28.1
[0741] As evidenced in Tables 67 and 68 above, there was no lag in
absorption of either oxycodone or acetaminophen for any of the
Treatments. The dose-normalized pharmacokinetic parameters of
oxycodone following single and multiple doses of the extended
release formulation disclosed herein (Treatment A) were equivalent
to the commercially-available oxycodone tablet (Treatment B) with
respect to Cmax, AUC0-t, and AUC0-inf (single dose). There was also
no significant difference in the median Tmax of oxycodone between
Treatment A and Treatment B. In addition, there was no lag (median
tlag=0) in the plasma oxycodone levels for any of the
treatments.
[0742] Similarly, dose-normalized pharmacokinetic parameters of
acetaminophen following a single dose of the extended release
formulation disclosed herein (Treatment A) were equivalent to the
commercially-available tramadol/acetaminophen tablet (Treatment C)
with respect to C.sub.max, AUC.sub.0-t, and AUC.sub.0-inf. The
median T.sub.max of acetaminophen from Treatment A occurred
significantly earlier than the median T.sub.max for Treatment C.
Further, the plasma concentrations of acetaminophen in subjects who
were administered Treatment A were less than 1000 ng/mL 12 hours
post-dose. There was also no lag (median t.sub.lag=0) in the plasma
acetaminophen levels for any of the treatments.
[0743] Consequently, the comparable PK findings between treatment
groups in this study support the use of the extended release
formulation containing 7.5 mg oxycodone and 325 mg acetaminophen
disclosed herein (Treatment A) for acute pain over the proposed
12-hour dosing interval.
Example 31
Multiple Dose Pharmacokinetic Analysis of an Extended Release
Formulation of Oxycodone and Acetaminophen Administered Under
Fasted Conditions
[0744] An open-label, randomized, multiple-dose, four-period
crossover study to evaluate the pharmacokinetics, bioavailability
and safety a bilayer tablet formulation comprising an immediate
release portion and an extended release portion containing 7.5 mg
oxycodone and 325 mg acetaminophen (see selected example from Chart
No. 1) with either a commercially-available tablet containing 15 mg
oxycodone or a commercially-available tablet containing 37.5 mg
tramadol and 325 mg acetaminophen was conducted in subjects in a
fasted state. All treatments were then compared against a
commercially-available immediate release tablet containing 7.5 mg
oxycodone and 325 mg acetaminophen.
[0745] The subjects were randomly assigned to 1 of 4 treatment
sequences: A/D/B/C, B/A/C/D, C/B/D/A, or D/C/A/B. Treatments A, B,
C, and D were as follows: [0746] Treatment A: 2 tablets of a
bilayer tablet formulation disclosed herein containing 7.5 mg
oxycodone and 325 mg acetaminophen administered orally, 1 tablet at
a time, Q12 h for 4.5 days (9 doses). [0747] Treatment B: 1 tablet
of a commercially-available tablet containing 15 mg oxycodone
administered orally Q6 h for 4.5 days (18 doses). [0748] Treatment
C: 1 tablet of a commercially-available tablet containing 37.5 mg
tramadol and 325 mg acetaminophen administered orally Q6 h for 4.5
days (18 doses). [0749] Treatment D: 1 tablet of a
commercially-available immediate release tablet containing 7.5 mg
oxycodone and 325 mg acetaminophen administered orally Q6 h for 4.5
days (18 doses).
[0750] For Treatment A, at Hour 0 on Day 1 and Hour 96 on Day 5,
subjects received 2 tablets of the extended release tablet
formulation disclosed herein containing 7.5 mg oxycodone and 325 mg
acetaminophen after an overnight fast of at least 10 hours.
Subjects received subsequent doses of Treatment A administered Q12
h at Hours 12, 24, 36, 48, 60, 72, and 84 after a fast of at least
1 hour.
[0751] For Treatments B, C, and D, at Hour 0 on Day 1 and Hour 96
on Day 5, subjects received 1 tablet of either a
commercially-available tablet containing 15 mg oxycodone, a
commercially-available tablet containing 37.5 mg tramadol and 325
mg acetaminophen, or a commercially-available immediate release
tablet containing 7.5 mg oxycodone and 325 mg acetaminophen after
an overnight fast of at least 10 hours. Subjects received
subsequent doses of Treatments B, C, or D administered Q6 h at
Hours 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84, 90,
and 102 after a fast of at least 1 hour.
[0752] During each period, serial blood samples for pharmacokinetic
analysis of oxycodone and acetaminophen were collected before
dosing and up to 12 hours after dosing. For steady-state analysis,
blood samples were collected on Days 2 through 4 before the morning
dose of study drug and on Day 5 before dosing and through 132 hours
(Day 6).
[0753] The mean pharmacokinetic parameters for oxycodone at steady
states are presented in Table 69, and the mean oxycodone plasma
concentration versus time profiles are presented in FIG. 50. As
evidenced in Table 69, there was no lag in absorption of oxycodone
for Treatments A, B, and D. The median Tmaxss for oxycodone was
significantly shorter for Treatment A than for Treatment D.
Moreover, the total systemic and peak exposure of oxycodone for
Treatment A at steady state was equivalent to Treatment B when
measured by Cmaxss, Cminss, and AUC0-12 hss on Day 5. A patient's
exposure to oxycodone (AUC0-12 hss) and (Cmaxss) of Treatment A
over the dosing interval at steady state was bioequivalent to
Treatment B. The Cmaxss, Cminss, Cavgss, and AUC0-12 hss of
oxycodone for Treatment A was also equivalent to Treatment D.
TABLE-US-00083 TABLE 69 Mean Pharmacokinetic Parameters for
Oxycodone at Steady State Treatment A Treatment B Treatment D (2
tablets Q12h) (1 tablet Q6h) (1 tablet Q6h) Parameter (n = 24) (n =
24) (n = 24) AUC.sub.0-12 h.sup.ss (ng h/mL) 208.34 (45.34) 376.88
(83.90) 191.54 (42.81) C.sub.avg.sup.ss (ng/mL) 17.36 (3.78) 31.41
(6.99) 15.96 (3.57) C.sub.max.sup.ss (ng/mL) 24.00 (5.38) 45.15
(10.54) 26.32 (6.18) C.sub.min.sup.ss (ng/mL) 9.31 (2.39) 19.91
(4.93) 8.81 (2.40) DFL (%) 83.89 (17.58) 79.94 (19.83) 110.90
(33.39) Swing 1.65 (0.58) 1.32 (0.50) 2.13 (0.94) T.sub.max.sup.ss
(h).sup.a 3.00 (1.00, 5.92) 3.00 (1.00, 12.00) 7.25 (0.50, 8.13)
Days 5 through 6 K.sub.el (1/h) 0.1318 (0.0223) 0.1525 (0.0206)
0.1517 (0.0205) t.sub.1/2 (h) 5.40 (0.87) 4.62 (0.59) 4.65 (0.62)
.sup.aFor T.sub.max and t.sub.lag, the median (minimum, maximum)
values are presented.
[0754] The mean pharmacokinetic parameters for acetaminophen at
steady state are presented in Table 70, and the mean acetaminophen
plasma concentration versus time profiles are presented in FIG. 51.
As evidenced in Table 70, no significant difference in Tmaxss for
acetaminophen was observed between Treatments A, C, and D. Further,
the dose-normalized pharmacokinetic parameters of acetaminophen for
the extended release formulation disclosed herein (Treatment A)
were equivalent to the commercially-available
tramadol/acetaminophen tablet (Treatment C) with respect to Cmaxss,
Cavgss, and AUC0-12 hss. The dose-normalized Cminss of
acetaminophen for Treatment A was approximately 21% lower than
Cminss of acetaminophen for Treatment C, and 22% lower than
C.sub.min.sup.ss of acetaminophen for Treatment D. In contrast, the
dose-normalized C.sub.min.sup.ss of acetaminophen for Treatment C
was equivalent to the C.sub.min.sup.ss of acetaminophen for
Treatment D.
[0755] The degree of fluctuation of and swing in the plasma
concentrations of acetaminophen were also comparable between
Treatments A, C, and D. In addition, the plasma concentrations of
acetaminophen in subjects who were administered Treatment A
decreased below 1000 ng/mL between doses.
TABLE-US-00084 TABLE 70 Mean Pharmacokinetic Parameters for
Acetaminophen at Steady State Treatment A Treatment C Treatment D
(2 tablets Q12h) (1 tablet Q6h) (1 tablet Q6h) Parameter (n = 24)
(n = 24) (n = 24) AUC.sub.0-12 h.sup.ss 28160.40 (5807.09) 29711.92
(5427.37) 29284.22 (5477.73) (ng h/mL) C.sub.avg.sup.ss (ng/mL)
2346.70 (483.92) 2475.99 (452.28) 2440.35 (456.48) C.sub.max.sup.ss
(ng/mL) 4792.50 (1132.40) 5078.33 (1189.70) 4876.67 (1383.08)
C.sub.min.sup.ss (ng/mL) 852.75 (273.25) 1070.92 (367.35) 1069.13
(291.83) DFL (%) 169.13 (39.83) 163.90 (47.17) 155.25 (38.77) swing
5.08 (2.07) 4.22 (2.14) 3.81 (1.63) T.sub.max.sup.ss (h).sup.a 1.00
(0.50, 4.00) 0.88 (0.25, 8.00) 0.75 (0.25, 8.00) Days 5 through 6
K.sub.el (1/h) 0.1072 (0.0285) 0.1355 (0.0279) 0.1201 (0.0338)
t.sub.1/2 (h) 6.90 (1.76) 5.32 (1.10) 6.21 (1.79) .sup.aFor
T.sub.max and t.sub.lag, the median (minimum, maximum) values are
presented.
[0756] Thus, the comparable PK findings between treatment groups in
this study support the use of the extended release formulation
containing 7.5 mg oxycodone and 325 mg acetaminophen disclosed
herein (Treatment A) for acute pain over the proposed 12-hour
dosing interval.
Example 32
Clinical Half-Value Duration Analysis for Oxycodone After Single
and Multiple Doses of Controlled-Release Oxycodone/Acetaminophen
(CR OC/APAP) Tablets
[0757] Controlled-release (CR) formulations are designed to reduce
peak-to-trough fluctuations in plasma concentrations of
medications, which may result in lower peak concentrations and
potential reduction in the incidence and/or intensity of adverse
events. Conventional pharmacokinetic (PK) measures, such as maximum
plasma concentration (C.sub.max) and time to C.sub.max (T.sub.max),
alone may not sufficiently describe the characteristics of CR
formulations. Half-value duration (HVD) does not provide direct
information about a medication's duration of action; however, it
has been considered a clinical correlate of the in vivo duration of
action of a CR medication and as a complementary measure to
traditional PK measures to more fully describe the performance
characteristics of CR formulations. HVD is defined as the period of
time during a dosing cycle that plasma concentrations are equal to
or above the half of the maximum concentration (.gtoreq.50%
C.sub.max).
[0758] A study analyzing the PK data from two randomized,
open-label, crossover studies (1 single-dose and 1 multiple-dose
study) was conducted. PK data were analyzed for 29 subjects in the
single-dose study and 24 subjects in the multiple-dose study.
Demographics and baseline characteristics of subjects were similar
in the 2 studies. Participants meeting any of the following
criteria were excluded from the study: current recreational drug
use; history of abuse/addiction or recent illicit drug use (within
2 years) or nicotine use (within 6 months); history of any
condition that may interfere with the absorption, distribution,
metabolism, or excretion of study medication; or history of gastric
bypass or gastric band surgery.
[0759] The following treatments were administered under fasted
conditions: [0760] Oral doses of CR OC/APAP (7.5 mg OC/325 mg APAP)
(see selected example from Chart No. 1) administered as 2 tablets
(total dose: 15 mg/650 mg) taken once (single-dose study) or 2
tablets taken twice daily every 12 hours over 4.5 days for 9 doses
(multiple-dose study) [0761] Oral doses of commercially available
IR OC/APAP 7.5 mg/325 mg (see selected example from Chart No. 1),
administered during a separate trial period as 1 tablet every 6
hours for 2 doses (single-dose study) or 1 tablet every 6 hours
over 4.5 days for 18 doses (multiple-dose study)
[0762] Blood samples for PK analysis were collected up to 36 hours
(single-dose study) or up to 132 hours (after the hour-0 dose;
multiple-dose study). Plasma oxycodone concentrations were
determined using a validated liquid chromatography/tandem mass
spectrometry (LC-MS/MS) method. HVD, degree of fluctuation,
C.sub.max, T.sub.max, and area under the concentration-time curve
(AUC) were calculated for oxycodone. Safety and tolerability were
monitored throughout each study.
[0763] Individual plasma concentration versus actual time data were
used to estimate the PK parameters of oxycodone by standard
noncompartmental methods. In both the single-dose and multiple-dose
studies, analysis of variance was performed to compare treatments
using the natural log-transformed, dose-normalized (amount absorbed
corrected by dose administered) PK parameters (C.sub.max and AUC)
or natural log-transformed PK parameters (degree of fluctuation) as
the dependent variables, with sequence, treatment, and period as
fixed effects and subjects nested within sequences as random
effect. HVD of oxycodone after CR OC/APAP (single- or
multiple-dose) was compared with that after IR OC/APAP using paired
2-tailed t tests. Descriptive statistics and paired t tests were
calculated for the percentage difference in HVD relative to the IR
product (% RDHVD). The % RDHVD was calculated as the average
percent difference in HVD for CR OC/APAP relative to IR OC/APAP for
individual subjects.
[0764] FIG. 52 presents the plasma oxycodone concentration over
time during the single-dose study. FIG. 52 further presents the HVD
for the CR and IR formulations administered. Moreover, Table 71
provides a summary of the PK measures for oxycodone in the initial
12 hours after dosing, for both the single-dose study and the
multi-dose study. In the single-dose study, the HVD of oxycodone
was significantly greater for CR OC/APAP compared with IR OC/APAP
(9.65 h vs 5.94 h, difference of 3.71 h, P<0.0001). There was a
significant increase in HVD by 77.5% for CR OC/APAP versus IR
OC/APAP (P<0.0001). AUC values for oxycodone after
administration of CR OC/APAP and IR OC/APAP (dose-normalized) were
comparable. The C.sub.max of oxycodone (normalized for dose) was
27% lower for CR OC/APAP compared with IR OC/APAP during the
initial 12 hours after dosing. Oxycodone T.sub.max was observed at
4 hours for CR OC/APAP and 8 hours (2 hours after the second dose)
for IR OC/APAP.
TABLE-US-00085 TABLE 71 Pharmacokinetic Measures for Oxycodone,
Initial 12 Hours After Dosing Multiple-Dose Parameter, Single-Dose
Study Study, Day 1 mean (SD) CR OC/APAP IR OC/APAP CR OC/APAP IR
OC/APAP C.sub.max, ng/mL 14.28 (2.9) 19.42 (4.6) 16.04 (3.6) 19.83
(5.1) T.sub.max, h.sup.a 4.00 (0.75-12.0) 8.00 (0.5-12.0) 3.00
(0.5-8.0) 8.00 (0.5-10.0) AUC, ng h/mL 169.34 (37.0).sup.b 171.53
(34.1).sup.b 136.14 (23.7).sup.c 132.45 (22.8).sup.c HVD, h 9.65
(2.8) 5.94 (2.2) 7.9 (1.7) 5.54 (2.5) .sup.aMedian (range)
.sup.bAUC.sub.0-inf .sup.cAUC.sub.0-12 h
[0765] FIG. 53 presents the plasma oxycodone concentration versus
time during the first day of the multi-dose study. FIG. 53 further
presents the HVD for the CR and IR formulations administered.
Moreover, as explained above, Table 71 provides a summary of the PK
measures for oxycodone in the initial 12 hours after dosing, for
both the single-dose study and the multi-dose study. In the
multi-dose study, the HVD for oxycodone over the dosing interval on
day 1 was significantly greater for CR OC/APAP compared with IR
OC/APAP (7.90 h vs 5.54 h, difference of 2.35 h, P<0.0001).
There was a significant increase in HVD by 70.5% for CR OC/APAP
versus IR OC/APAP (P=0.0002). After initial dosing (day 1) in the
multiple-dose study, the C.sub.max of oxycodone was lower for CR
OC/APAP compared with IR OC/APAP. AUC was similar between
treatments.
[0766] FIG. 54 presents the steady-state plasma oxycodone
concentration versus time during day 5 of the multi-dose study.
FIG. 54 further presents the HVD for the CR and IR formulations
administered. Furthermore, Table 72 presents a summary of the PK
measures for oxycodone for day 5 of the multi-dose study. HVD at
steady state (day 5) was significantly greater for CR OC/APAP
compared with IR OC/APAP (7.85 h vs 5.79 h, difference of 2.06 h,
P=0.0008). There was a significant increase in HVD by 65.6% for CR
OC/APAP versus IR OC/APAP (P=0.0002). C.sub.max and AUC for
oxycodone were similar after steady-state dosing of CR OC/APAP and
IR OC/APAP. Degree of fluctuation at steady state was 23% lower for
CR OC/APAP compared with IR OC/APAP (84% vs 111%).
TABLE-US-00086 TABLE 72 Steady-State Pharmacokinetic Measures for
Oxycodone (day 5) Parameter CR OC/APAP IR OC/APAP C.sub.max,
ng/mL.sup.a 24.00 (5.4) 26.32 (6.2) T.sub.max, h.sup.b 3.00
(1.0-5.9) 7.25 (0.5-8.13) AUC.sub.0-12 h, ng h/mL.sup.a,c 208.34
(45.3) 191.54 (42.8) Degree of fluctuation, % 83.89 (17.6) 110.9
(33.4) HVD, h.sup.a 7.85 (1.4) 5.79 (2.8) .sup.aMean (SD)
.sup.bMedian (range) .sup.cMean exposure within 0-12 hours after
the hour-96 dose (day 5, at steady state).
[0767] Table 73 summarizes the most frequently occurring
treatment-emergent adverse events (TEAEs) reported during the
single-dose and multi-dose studies. The most frequently reported
TEAEs following administration of CR OC/APAP were nausea, vomiting,
pruritus, dizziness, and headache.
TABLE-US-00087 TABLE 73 Most Frequently Occurring
Treatment-Emergent Adverse Events (.gtoreq.5% with CR OC/APAP)
Single-Dose Study Multiple-Dose Study Treatment-Emergent CR IR CR
IR Adverse Event, n OC/APAP OC/APAP OC/APAP OC/APAP (%) (n = 39) (n
= 40) (n = 33) (n = 31) Any TEAE 9 (23.1) 15 (37.5) 15 (45.5) 20
(64.5) Nausea 5 (12.8) 9 (22.5) 8 (24.2) 9 (29.0) Dizziness 3 (7.7)
4 (10.0) 4 (12.1) 4 (12.9) Vomiting 1 (2.6) 1 (2.5) 7 (21.2) 5
(16.1) Headache 1 (2.6) 3 (7.5) 5 (15.2) 3 (9.7) Somnolence 3 (7.7)
3 (7.5) 1 (3.0) 1 (3.2) Pruritus 1 (2.6) 1 (2.5) 7 (21.2) 2 (6.5)
Feeling hot 1 (2.6) 2 (5.0) 2 (6.1) 2 (6.5) Abdominal pain 1 (2.6)
0 (0.0) 2 (6.1) 3 (9.7)
[0768] The results of this study demonstrate that administration of
CR OC/APAP resulted in a greater time above 50% of the C.sub.max
for oxycodone compared with administration of IR OC/APAP. At steady
state, CR OC/APAP was associated with significantly less
fluctuation in plasma oxycodone concentrations compared with IR
OC/APAP. Traditional PK measures indicate equivalent or lower
C.sub.max and equivalent AUC for oxycodone after administration of
CR OC/APAP compared with IR OC/APAP. CR OC/APAP was generally well
tolerated, with TEAEs that were consistent with those associated
with opioid therapy. The results of this PK analysis support the
administration of CR OC/APAP every 12 hours for the management of
moderate to severe acute pain.
Example 33
Dose Proportionality and Linearity of Acetaminophen after Single or
Multiple Oral Doses of Controlled-Release Oxycodone/Acetaminophen
(CR OC/APAP) Tablets
[0769] Data were pooled from randomized, crossover, single- and
multiple-dose studies conducted in healthy adults (aged 18-55
years) to evaluate the dose proportionality and dose linearity of
the APAP component of CR OC/APAP when administered as 1, 2, or 4
tablets (325 mg, 650 mg, or 1300 mg APAP, respectively). CR OC/APAP
tablets employ a dual-layer biphasic delivery mechanism that, when
administered as 2 tablets, include an immediate-release component
delivering 3.75 mg OC/325 mg APAP and an extended-release component
delivering 11.25 mg OC/325 mg APAP. (See selected example from
Chart No. 1)
[0770] The following treatments were administered under fasted
conditions: [0771] Single-dose studies: 1, 2, or 4 tablets of CR
OC/APAP (325 mg, 650 mg, or 1300 mg APAP, respectively) (see
selected example from Chart No. 1) administered orally once [0772]
Multiple-dose studies: 1 or 2 tablets of CR OC/APAP (325 mg or 650
mg APAP, respectively) (see selected example from Chart No. 1)
administered orally every 12 hours for 4.5 days (9 doses)
[0773] One single-dose study (highest dosage) enrolled healthy
recreational drug users; all other studies enrolled healthy
subjects with specific exclusions for drug use.
[0774] Blood samples for plasma analysis of APAP were collected up
to 48 hours after dosing in single-dose studies and up to 144 hours
after the hour-0 dose in multiple-dose studies. Area under the
plasma APAP concentration-time curve from time 0 extrapolated to
infinity (AUC.sub.0-inf) and maximum plasma concentration
(C.sub.max)) were compared across dose levels of CR OC/APAP. Dose
linearity for CR OC/APAP was assessed; linearity indicates that
drug disposition (absorption, distribution, metabolism, and
excretion) are constant whatever the dose. For a linear PK system,
the measures of exposure, such as maximal blood concentration
(C.sub.max) or area under the curve from 0 to infinity (AUC) on the
y-axis, are linearly (i.e., by a straight line) related to dose on
the x-axis. Dose proportionality for CR OC/APAP was assessed; dose
proportionality occurs when increases in the administered dose are
accompanied by proportional increases in a measure of exposure,
such as AUC or C.sub.max.
[0775] Individual plasma concentration versus actual time data were
used to estimate the PK parameters of APAP by standard
non-compartmental methods. Non-transformed and log-transformed data
for AUC.sub.0-inf and C.sub.max were evaluated by analysis of
variance (ANOVA) using the SAS mixed procedure to verify no effect
of study; data were tested for normality. AUC.sub.0-inf and
C.sub.max were divided by dose (dose-normalized) for dose
proportionality analyses. Dose normalization (calculated as plasma
concentration divided by dose) was utilized to compare
concentration across different dosage strengths. Dose linearity and
proportionality were determined using linear regression of
non-transformed data, including 95% confidence intervals (CIs) and
95% prediction limits. Slope, y-intercept, and R.sup.2 were
calculated. The slope and the intercept together define the linear
relationship between dose and AUC, or dose and C.sub.max. The
coefficient of determination, R.sup.2, represents the proportion of
variability in a data set that is accounted for by a statistical
model.
[0776] FIG. 55 presents the plasma APAP concentration versus time
following single-dose administration of CR OC/APAP. FIG. 56
presents the plasma APAP concentration versus time following
multi-dose administration of CR OC/APAP. FIG. 57 presents the
steady-state plasma APAP concentration versus time following
multi-dose administration of CR OC/APAP (hours 96 to 144 on day 5,
relative to the start of dosing at Hour-0). For both the
single-dose and multiple-dose studies, plasma APAP concentrations
rose rapidly and in a dose-dependent manner. In multiple-dose
studies, steady-state APAP levels were reached by day 2 (24 hours
after first dose) with 2-tablet dosing and day 4 with 1-tablet
dosing.
[0777] Table 74 summarizes the linearity of APAP PK parameters in
the single-dose and multi-dose studies. As shown in Table 74, after
both single and multiple doses of CR OC/APAP, APAP AUC.sub.0-inf
and C.sub.max were linear with respect to dose.
TABLE-US-00088 TABLE 74 Linearity of APAP Pharmacokinetic
Parameters Parameter Single-Dose Multiple-Dose (95% CI) (N = 119)
(N = 57) AUC.sub.0-inf Slope 41.021 40.177 (36.915, 45.126)
(32.089, 48.265) y-Intercept 4024.292 2249.134 (627.210, 7421.373)
(-2227.061, 6725.329) R.sup.2 0.6657 0.5255 C.sub.max Slope 6.336
7.079 (5.637, 7.035) (5.125, 9.032) y-Intercept 467.019 816.140
(-123.280, 1057.318) (-265.031, 1897.312) R.sup.2 0.6080 0.3708
[0778] Table 75 presents the proportionality of APAP PK parameters
(dose normalized). Dose-normalized APAP AUC.sub.0-inf and C.sub.max
values after single and multiple doses of CR OC/APAP were
proportional to dose as indicated by linear regression with slopes
approximately equal to zero. Tests for dose proportionality showed
that the slope of dose-adjusted AUC.sub.0-inf and C.sub.max were
approximately equal to zero for both single doses (-0.007 and
-0.001, respectively) and at steady state (-0.011 and -0.004,
respectively).
TABLE-US-00089 TABLE 75 Proportionality of APAP Pharmacokinetic
Parameters (Dose Normalized) Parameter Single-Dose Multiple-Dose
(95% CI) (N = 119) (N = 57) AUC.sub.0-inf Slope -0.007 (-0.013,
-0.002) -0.011 (-0.026, 0.005) y-Intercept 52.943 (48.255, 57.631)
50.557 (42.124, 58.990) R.sup.2 0.0321 0.0214 C.sub.max Slope
-0.001 (-0.002, 0.000) -0.004 (-0.007, 0.000) y-Intercept 7.877
(7.088, 8.665) 10.845 (8.905, 12.786) R.sup.2 0.0219 0.0517
[0779] Safety and tolerability in each study was assessed using
standard measures, including adverse event monitoring and clinical
laboratory testing. Tables 76 and 77 present the most common
treatment-emergent adverse events (TEAEs) in the single-dose and
multi-dose studies, respectively. TEAEs in the single-dose studies
(Table 76) and the multiple-dose studies (Table 77) were consistent
with those expected with opioid analgesic therapy. The most common
TEAEs at the dose levels tested were: [0780] 1 tablet (7.5 mg
OC/325 mg APAP): nausea (single-dose studies) and headache
(multiple-dose studies) [0781] 2 tablets (15 mg OC/650 mg APAP):
nausea (single- and multiple-dose studies) [0782] 4 tablets (30 mg
OC/1300 mg APAP): pruritus (single-dose study in healthy
recreational drug users)
TABLE-US-00090 [0782] TABLE 76 Most Common Treatment-Emergent
Adverse Events (.gtoreq.5% of patients), Single-Dose Studies CR CR
OC/APAP OC/APAP 1 tablet CR OC/APAP 4 tablets (7.5/325 2 tablets
(30/1300 mg) (15/650 mg) mg) TEAE, n (%) Study 1 Study 1 Study 2
Study 3* Study 3* Dizziness 1 (2.6) 4 (9.8) 3 (7.7) 0 0 Euphoric 1
(2.6) 3 (7.3) 1 (2.6) 0 0 mood Headache 1 (2.6) 8 (19.5) 1 (2.6) 4
(6.9) 3 (5.4) Nausea 4 (10.3) 12 (29.3) 5 (12.9) 0 6 (10.7)
Pruritus 0 3 (7.3) 1 (2.6) 2 (3.4) 8 (14.3) Vomiting 2 (5.1) 7
(17.1) 1 (2.6) 1 (1.7) 2 (3.6) Somnolence 2 (5.1) 5 (12.2) 3 (7.7)
0 4 (7.1) *Subjects enrolled in Study 3 were healthy recreational
drug users.
TABLE-US-00091 TABLE 77 Most Common Treatment-Emergent Adverse
Events (.gtoreq.5% of patients), Multiple-Dose Studies CR OC/APAP
CR OC/APAP 1 tablet 2 tablets (7.5/325 mg) (15/650 mg) TEAE, n (%)
Study 1 Study 1 Study 2 Abdominal pain 0 3 (7.3) 0 Dizziness 5
(12.5) 5 (12.2) 4 (12.1) Headache 8 (20.0) 0 5 (15.2) Hiccups 0 4
(9.8) 0 Infrequent bowel 2 (5) 5 (12.2) 0 movements Nausea 5 (12.5)
12 (29.3) 8 (24.2) Pruritus 5 (12.5) 10 (24.4) 7 (21.2) Somnolence
5 (12.5) 5 (12.2) 0 Vomiting 1 (2.5) 5 (12.2) 7 (21.2)
[0783] Most changes in serum chemistry and hematology were not
considered by the investigator to be clinically meaningful, and
none affected subject safety. One subject (0.8%) in a single-dose
study had abnormal elevated bilirubin, which was considered by the
investigator to be mild and possibly related to study medication.
One subject (2%) in a multiple-dose study had anemia, which was not
considered related to study medication.
[0784] The results of this study demonstrate that APAP plasma
concentrations following single- and multiple-dose administration
of CR OC/APAP (across a range of 1, 2, and 4 tablets) were linear
and proportional with respect to dose. All doses were generally
well tolerated, with the most frequently occurring TEAEs varying
with dose. TEAEs were consistent with those expected with opioid
analgesic therapy. These findings demonstrate dose proportionality
and dose linearity of the APAP component of CR OC/APAP up to 30
mg/1300 mg.
Example 34
Dose Proportionality and Linearity of Oxycodone after Single or
Multiple Oral Doses of Controlled-Release Oxycodone/Acetaminophen
(CR OC/APAP) Tablets
[0785] Data were pooled from randomized, crossover, single- and
multiple-dose studies conducted in healthy adults (aged 18-55
years) to evaluate the dose proportionality and dose linearity of
the oxycodone component of CR OC/APAP when administered as 1, 2, or
4 tablets (7.5 mg, 15 mg, or 30 mg oxycodone, respectively). CR
OC/APAP tablets employ a dual-layer biphasic delivery mechanism
that, when administered as 2 tablets, include an immediate-release
component delivering 3.75 mg OC/325 mg APAP and an extended-release
component delivering 11.25 mg OC/325 mg APAP. (See selected example
from Chart No. 1)
[0786] The following treatments were administered under fasted
conditions: [0787] Single-dose studies: 1, 2, or 4 tablets of CR
OC/APAP (7.5 mg, 15 mg, or 30 mg oxycodone, respectively) (see
selected example from Chart No. 1) administered orally once [0788]
Multiple-dose studies: 1 or 2 tablets of CR OC/APAP (7.5 mg or 15
mg oxycodone, respectively) (see selected example from Chart No. 1)
administered every 12 hours for 4.5 days (9 doses)
[0789] One single-dose study (highest dosage) enrolled healthy
recreational drug users; all other studies enrolled healthy
subjects with specific exclusions for drug use.
[0790] Blood samples for plasma analysis of oxycodone were
collected up to 48 hours after dosing in single-dose studies and up
to 144 hours after the hour-0 dose in multiple-dose studies. Area
under the plasma oxycodone concentration-time curve from time 0
extrapolated to infinity (AUC.sub.0-inf) and maximum plasma
concentration (C.sub.max)) were compared across dose levels of CR
OC/APAP. Dose linearity for CR OC/APAP was assessed; linearity
indicates that drug disposition processes (absorption,
distribution, metabolism, and excretion) are constant whatever the
dose. For a linear PK system, the measures of exposure, such as
maximal blood concentration (C.sub.max) or area under the curve
from 0 to infinity (AUC) on the y-axis, are linearly (i.e., by a
straight line) related to dose on the x-axis. Dose proportionality
for CR OC/APAP was assessed; dose proportionality occurs when
increases in the administered dose are accompanied by proportional
increases in a measure of exposure, such as AUC or C.sub.max.
[0791] Individual plasma concentration versus actual time data were
used to estimate the PK parameters of oxycodone by standard
non-compartmental methods. Non-transformed and log-transformed data
for AUC.sub.0-inf and C.sub.max were evaluated by analysis of
variance (ANOVA) using the SAS mixed procedure to verify no effect
of study; data were tested for normality. AUC.sub.0-inf and
C.sub.max were divided by dose (dose-normalized) for dose
proportionality analyses. Dose normalization (calculated as plasma
concentration divided by dose) was utilized to compare
concentration across different dosage strengths. Dose linearity and
proportionality were determined using linear regression of
non-transformed data, including 95% confidence intervals (CIs) and
95% prediction limits. Slope, y-intercept, and R.sup.2 were
calculated. The slope and the intercept together define the linear
relationship between dose and AUC, or dose and C.sub.max. The
coefficient of determination, R.sup.2, represents the proportion of
variability in a data set that is accounted for by a statistical
model.
[0792] FIG. 58 presents the plasma oxycodone concentration versus
time following single-dose administration of CR OC/APAP. FIG. 59
presents the plasma oxycodone concentration versus time following
multi-dose administration of CR OC/APAP. FIG. 60 presents the
steady-state plasma oxycodone concentration versus time following
multi-dose administration of CR OC/APAP (hours 96 to 144 on day 5,
relative to the start of dosing at Hour-0). For both the
single-dose and multiple-dose studies, plasma oxycodone
concentrations rose rapidly and were sustained in a dose-dependent
manner. In multiple-dose studies, steady-state oxycodone levels
were reached by day 2 and 3 (24-48 hours after first dose) with
2-tablet dosing and day 4 with 1-tablet dosing.
[0793] Table 78 summarizes the linearity of oxycodone PK parameters
in the single-dose and multi-dose studies. As shown in Table 78,
after both single and multiple doses of CR OC/APAP, oxycodone
AUC.sub.0-inf and C.sub.max were linear with respect to dose.
TABLE-US-00092 TABLE 78 Linearity of Oxycodone Pharmacokinetic
Parameters Parameter Single-Dose Multiple-Dose (95% CI) (N = 119)
(N = 57) AUC.sub.0-inf Slope 11.093 (10.022, 12.165) 14.151
(11.477, 16.824) y-Intercept 7.202 (-13.583, 27.987) -3.774
(-37.919, 30.371) R.sup.2 0.6767 0.5570 C.sub.max Slope 1.050
(0.964, 1.136) 1.640 (1.308, 1.972) y-Intercept -0.417 (-2.090,
1.256) 0.362 (-3.877, 4.602) R.sup.2 0.7384 0.5229
[0794] Table 79 presents the proportionality of oxycodone PK
parameters (dose normalized). Dose-normalized oxycodone
AUC.sub.0-inf and C.sub.max values after single and multiple doses
of CR OC/APAP were proportional to dose as indicated by linear
regression with slopes approximately equal to zero. Tests for dose
proportionality showed that the slope of dose-adjusted
AUC.sub.0-inf and C.sub.max were approximately equal to zero for
both single doses (-0.024 and -0.001, respectively) and at steady
state (0.033 and -0.003, respectively).
TABLE-US-00093 TABLE 79 Proportionality of Oxycodone
Pharmacokinetic Parameters (Dose Normalized) Parameter Single-Dose
Multiple-Dose (95% CI) (N = 119) (N = 57) AUC.sub.0-inf Slope
-0.024 (-0.079, 0.030) 0.033 (-0.180, 0.247) y-Intercept 12.015
(10.950, 13.081) 13.397 (10.665, 16.129) R.sup.2 0.0038 0.0011
C.sub.max Slope -0.001 (-0.005, 0.004) -0.003 (-0.029, 0.023)
y-Intercept 1.041 (0.953, 1.129) 1.712 (1.377, 2.047) R.sup.2
0.0004 0.0006
[0795] Safety and tolerability in each study was assessed using
standard measures, including adverse event monitoring and clinical
laboratory testing. Tables 80 and 81 present the most common
treatment-emergent adverse events (TEAEs) in the single-dose and
multi-dose studies, respectively. TEAEs in the single-dose studies
(Table 80) and the multiple-dose studies (Table 81) were consistent
with those expected with opioid analgesic therapy. The most common
TEAEs at the dose levels tested were: for 1 tablet (7.5 mg OC/325
mg APAP)--nausea (single-dose studies) and headache (multiple-dose
studies); for 2 tablets (15 mg OC/650 mg APAP)--nausea (single- and
multiple-dose studies); and for 4 tablets (30 mg OC/1300 mg
APAP)--pruritus (single-dose study in healthy recreational drug
users).
TABLE-US-00094 TABLE 80 Most Common Treatment-Emergent Adverse
Events (.gtoreq.5% of patients), Single-Dose Studies CR CR OC/APAP
CR OC/APAP OC/APAP Treatment-Emergent 1 tablet 2 tablets 4 tablets
Adverse (7.5/325 mg) (15/650 mg) (30/1300 mg) Event, n (%) Study 1
Study 1 Study 2 Study 3* Study 3* Dizziness 1 (2.6) 4 (9.8) 3 (7.7)
0 0 Euphoric mood 1 (2.6) 3 (7.3) 1 (2.6) 0 0 Headache 1 (2.6) 8
(19.5) 1 (2.6) 4 (6.9) 3 (5.4) Nausea 4 (10.3) 12 (29.3) 5 (12.9) 0
6 (10.7) Pruritus 0 3 (7.3) 1 (2.6) 2 (3.4) 8 (14.3) Vomiting 2
(5.1) 7 (17.1) 1 (2.6) 1 (1.7) 2 (3.6) Somnolence 2 (5.1) 5 (12.2)
3 (7.7) 0 4 (7.1) *Subjects enrolled in Study 3 were healthy
recreational drug users.
TABLE-US-00095 TABLE 81 Most Common Treatment-Emergent Adverse
Events (.gtoreq.5% of patients), Multiple-Dose Studies CR OC/APAP
CR OC/APAP 1 tablet 2 tablets Treatment-Emergent (7.5 mg/325 mg)
(15 mg/650 mg) Adverse Event, n (%) Study 1 Study 1 Study 2
Abdominal pain 0 3 (7.3) 0 Dizziness 5 (12.5) 5 (12.2) 4 (12.1)
Headache 8 (20.0) 0 5 (15.2) Hiccups 0 4 (9.8) 0 Infrequent bowel 2
(5) 5 (12.2) 0 movements Nausea 5 (12.5) 12 (29.3) 8 (24.2)
Pruritus 5 (12.5) 10 (24.4) 7 (21.2) Somnolence 5 (12.5) 5 (12.2) 0
Vomiting 1 (2.5) 5 (12.2) 7 (21.2)
[0796] The results of this study demonstrate that oxycodone plasma
concentrations following single- and multiple-dose administration
of CR OC/APAP (across a range of 1, 2, and 4 tablets) were linear
and proportional with respect to dose. All doses were generally
well tolerated and TEAEs were consistent with those expected with
opioid analgesic therapy. These findings demonstrate dose
proportionality and dose linearity of the oxycodone component of CR
OC/APAP up to 30 mg/1300 mg.
Example 35
Comparison of Subjective Drug Effects of Orally Administered
Controlled-Release Oxycodone/Acetaminophen (CR OC/APAP) Tablets
Versus Immediate-Release Oxycodone/Acetaminophen Tablets in
Recreational Users of Prescription Opioids
[0797] A single-center, randomized, double-blind, double-dummy,
active- and placebo-controlled, crossover study was conducted to
compare the extent to which CR OC/APAP intact, CR OC/APAP crushed,
and commercially-available IR OC/APAP formulations produce certain
subjective effects that have been associated with drug abuse in
recreational opioid users, such as drug liking, drug high, and good
drug effects. Pharmacodynamic (PD) parameters were assessed after
administration of intact and crushed CR OC/APAP and IR OC/APAP to
recreational opioid users. Participants included healthy adult male
and female nondependent, recreational opioid users who reported
occasions of recreational opioid use over the past year, including
occasion within the past 12 weeks.
[0798] Participants initially underwent a naloxone challenge test
to confirm a lack of physical dependence on opioids and a drug
discrimination test to determine that they could detect the
subjective effects of oxycodone. During the drug discrimination
test, all participants received single doses of IR OC/APAP (15
mg/650 mg) and placebo and reported on the subjective effects.
Participants who could not discriminate between active drug and
placebo or tolerate this single dose were excluded from enrollment.
A total of 107 participants entered the study, were checked into
the clinical facility, and completed the study inclusion phase.
Safety analyses were conducted in 61 participants who passed the
drug discrimination phase and entered the treatment phase. PK and
PD analyses were performed with data collected from the 55
participants who completed the assessment phase. Participants had a
mean age of 26 years and approximately 75% were male. 95% of
participants had a history of alcohol abuse and 67% had a history
of tobacco use.
[0799] The treatment phase included a total of 7 assessment
periods, with a 72-hour washout period between doses. During the
treatment phase, because of the history of prescription opioid
abuse in this population, IR OC/APAP was encapsulated for proper
blinding. To ensure blinding of all study treatments, participants
received matching placebos for each possible treatment
configuration so dose administration in each treatment period
consisted of 8 capsules and 4 tablets. For administration of the CR
OC/APAP, controlled-release tablets containing 7.5 mg OC/325 mg
APAP were used. (See selected example from Chart No. 1). During
each assessment period, participants received a single dose of one
of the 7 study treatments:
[0800] CR OC/APAP intact
[0801] High dose: 30 mg OC/1300 mg APAP (4 tablets)
[0802] Low dose: 15 mg OC/650 mg APAP (2 tablets)
[0803] IR OC/APAP intact
[0804] High dose: 30 mg OC/1300 mg APAP (4 tablets,
over-encapsulated)
[0805] Low dose: 15 mg OC/650 mg APAP (2 tablets,
over-encapsulated)
[0806] CR OC/APAP crushed (encapsulated)
[0807] High dose: 30 mg OC/1300 mg APAP (8 capsules)
[0808] IR OC/APAP crushed (encapsulated)
[0809] High dose: 30 mg OC/1300 mg APAP (4 capsules)
[0810] Placebo
[0811] The primary outcome measures were participant-reported
visual analog scale (VAS) scores for: drug liking--assessed on a
100-mm bipolar VAS (0 mm=Strong disliking; 50 mm=Neither like or
dislike; 100 mm=Strong liking); drug high--assessed on a 100-mm
unipolar VAS (0 mm=None; 100 mm=Extremely); and good drug
effects--assessed on a 100-mm unipolar VAS (0 mm=None; 100
mm=Extremely). Secondary outcome measures included pupillometry and
other subjective measures, such as Take Drug Again Assessment
(TDAA) bipolar 0- to 100-point VAS, Global Assessment of Overall
Drug Liking bipolar 0- to 100-point VAS, and Addiction Research
Center Inventory/Amphetamine Morphine Benzedrine Group (ARCI/AMBG)
4-point scale.
[0812] Peak drug effects (E.sub.max) was a primary pharmacodynamic
outcome analyzed. Higher E.sub.max values indicate greater maximum
perceived subjective effects. The time to E.sub.max (TE.sub.max)
was also analyzed. Lower TEmax values indicate shorter time to
maximum perceived subjective effects. The total area under the
effective curve (AUE), which measures the total subjective effect
over a specific time periods, with lower values indicating lesser
effect, was assessed at multiple time points from 0 to 12 hours.
Analyses of pharmacodynamic outcomes were performed using
least-squares mean (LSM) scores with 95% confidence intervals
(CIs), which were compared using a linear, mixed-model analysis of
variance (ANOVA) model with fixed effects for sequence, period, and
treatment, and a random effect for participants nested in the
sequence. Data were adjusted for multiple comparisons.
[0813] FIGS. 61-64 present the mean drug liking VAS scores over 12
hours. FIGS. 65-68 present the mean drug high VAS scores over 12
hours. As shown in FIGS. 61-68, all CR OC/APAP formulations
produced more delayed and lower mean peak positive effects
according to VAS scores for drug liking, drug high, and good drug
effects compared with IR OC/APAP. VAS scores for good drug effects
(results not shown in FIGS. 61-68) were similar to those for drug
high. FIG. 69 presents the least-squares mean E.sub.max for drug
liking for high-dose intact CR OC/APAP vs. IR OC/APAP. FIG. 70
presents the least-squares mean E.sub.max for drug high and good
drug effects for high-dose intact CR OC/APAP vs. IR OC/APAP.
E.sub.max values for these outcomes after the administration of
high-dose intact CR OC/APAP were significantly lower (P<0.001)
than for high-dose intact IR OC/APAP. (See FIGS. 69 and 70). FIG.
71 presents the least-squares mean TE.sub.max for drug liking, drug
high, and good drug effects for high-dose intact CR OC/APAP vs. IR
OC/APAP. TE.sub.max was delayed for high-dose intact CR OC/APAP
compared with IR OC/APAP, but only the difference for drug liking
(P<0.05) reached statistical significance. (See FIG. 71).
[0814] AUE values at early timepoints (i.e., 0-1 h and 0-2 h) for
these VAS ratings were also significantly lower for high-dose
intact CR OC/APAP compared with high-dose intact IR OC/APAP
(P<0.01 for each comparison). Comparisons between low-dose
intact CR OC/APAP and IR OC/APAP and high-dose crushed CR OC/APAP
and IR OC/APAP also demonstrated that the CR OC/APAP formulations
produced significantly lower E.sub.max scores for drug liking, drug
high, and good drug effects (P<0.001 for each comparison). As
shown in Table 82, Crushing CR OC/APAP did not increase these
effects and produced similar or less drug liking, drug high, and
good drug effects than the same dose of intact CR OC/APAP or IR
OC/APAP. Crushed CR OC/APAP had a significantly longer TE.sub.max
(P<0.02) and significantly lower AUE.sub.0-1h, AUE.sub.0-2h, and
AUE.sub.0-4h (P<0.02) for drug liking, drug high, and good drug
effects than the same dose of intact CR OC/APAP. Moreover,
secondary subjective measures (i.e., TDAA, global assessment of
overall drug liking, and ARCI/AMBG) produced results that were
consistent with the primary subjective measures.
TABLE-US-00096 TABLE 82 Pharmacodynamic Comparisons: Crushed vs
Intact CR OC/APAP High-Dose CR OC/APAP High-Dose Crushed vs IR
OC/APAP Intact vs High-Dose High-Dose Intact Crushed Drug Drug Good
Drug Drug Drug Good Drug Variable Liking High Effects Liking High
Effects E.sub.max LSM difference 12.3 33.4 28.5 3.1 5.3 8.5
Adjusted P <0.001 <0.001 <0.001 0.127 0.130 0.035
TE.sub.max LSM difference -1.1 -1.5 -1.4 -0.6 -1.0 -0.9 Unadjusted
P <0.001 <0.001 <0.001 0.012 <0.001 <0.001
AUE.sub.0-1 h LSM difference 10.2 22.4 23.0 5.6 9.8 12.6 Unadjusted
P 0.004 <0.001 <0.001 <0.001 <0.001 <0.001
AUE.sub.0-2 h LSM difference 23.1 65.6 59.0 14.4 27.5 31.1
Unadjusted P <0.001 <0.001 <0.001 <0.001 <0.001
<0.001 AUE.sub.0-4 h LSM difference 21.7 78.2 69.3 14.9 26.2
34.1 Unadjusted P <0.001 <0.001 <0.001 0.016 0.004 0.001
AUE.sub.0-8 h LSM difference 13.6 69.0 58.9 15.0 19.6 31.4
Unadjusted P 0.184 <0.001 <0.001 0.142 0.134 0.060
AUE.sub.0-12 h LSM difference 9.9 63.7 51.2 15.9 22.0 36.5
Unadjusted P 0.493 <0.001 0.014 0.214 0.153 0.077 *Drug liking
measured using a 100-mm bipolar VAS (0 = Strong disliking; 50 =
Neither like nor dislike; 100 = Strong liking). **Drug high and
good drug effects measured using a 100-mm unipoler (0 = None; 100 =
Extremely).
[0815] FIG. 72 presents the mean pupillometry scores over 12 hours.
Pupil size followed a similar time course as the subjective
effects. Notably, the delay in effects associated with crushing CR
OC/APAP was demonstrated in this physiologic effect.
[0816] The occurrence of adverse events (AEs) after administration
of study drug was also assessed. The most frequently observed AEs
were consistent with oxycodone-containing medications. AEs included
nausea, vomiting, and pruritus and were more common with IR OC/APAP
compared with CR OC/APAP.
[0817] The results of this study demonstrated that, within the
sample population of recreational prescription opioid users, CR
OC/APAP produced less drug liking, drug high, and good drug effects
compared with IR OC/APAP, a finding that may be associated with a
lower potential for abuse. In addition, crushing CR OC/APAP lowered
and delayed the effects compared with intact CR OC/APAP and IR
OC/APAP, an effect that is opposite to the intent of drug abusers.
This study showed that intact and crushed CR OC/APAP administered
at both low and high doses produced less drug liking, drug high,
and good drug effects compared with IR OC/APAP at the same doses.
The CR OC/APAP tablet technology includes a dual-layer, biphasic
delivery profile with an IR component and an ER component; when the
CR OC/APAP tablet is crushed, these 2 layers become mixed, delaying
the onset of the medication.
Example 36
Steady-State Pharmacokinetics of 1 and 2 Tablets a
Controlled-Release Oxycodone and Acetaminophen (CR OC/APAP)
Combination, Compared With Immediate-Release Oxycodone and
Acetaminophen
[0818] A single-center, open-label, randomized, phase 1,
multiple-dose, 3-period, 6-sequence, crossover study was conducted
to evaluate the steady-state PK and bioavailability of both the
oxycodone and APAP components of 1- or 2-tablet dosages of CR
OC/APAP administered every 12 hours over 4.5 days compared with the
1-tablet dosing of IR OC/APAP administered every 6 hours over 4.5
days. The study further assessed the dose proportionality of 1- and
2-tablet dosages of CR OC/APAP at steady state, and evaluated the
relative safety of CR OC/APAP compared with IR OC/APAP.
[0819] Participants in the study were normal healthy male or
non-lactating, non-pregnant female subjects aged 18 to 55 years
with body mass index of .gtoreq.9 to .ltoreq.30 kg/m and a minimum
weight of 130 lbs. Exclusion criteria included smoking or use of
nicotine containing products in the previous 6 months; history of
drug or alcohol use or positive urine test for drugs of abuse; use
of prescription or over-the-counter drugs within 14 days of study
check-in; history of drug allergy, hypersensitivity, or intolerance
of opioid drug products (including oxycodone) or APAP; history of
any condition that may interfere with the absorption, distribution,
metabolism, or excretion of study drug; or previous gastric bypass
or gastric band surgery. A total of 48 adults enrolled in the
studies. 33 (68.8%) completed all 3 treatment periods. Subjects
were randomized to receive the following treatments in a crossover
design under fasted conditions: [0820] Treatment A: CR OC/APAP, 1
tablet (7.5 mg OC/325 mg APAP) (see selected example from Chart No.
1) taken every 12 hours for 4.5 days (9 tablets total) [0821]
Treatment B: CR OC/APAP, 2 tablets (total, 15 mg OC/650 mg APAP)
(see selected example from Chart No. 1) taken every 12 hours for
4.5 days (18 tablets total) [0822] Treatment C:
commercially-available IR OC/APAP, 1 tablet (7.5 mg OC/325 mg APAP)
taken every 6 hours for 4.5 days (18 tablets total)
[0823] The study included a screening visit and 3 confinement
periods of approximately 7 days each, with a minimum of 14 days
between the start of each period, and a telephone follow-up period
of at least 7 days after study completion. Plasma samples were
collected at the following times up to 144 hours after dosing:
[0824] Day 1: pre-dose, and 15, 30, and 45 minutes and 1, 2, 3, 4,
6, 7, 8, 10, and 12 hours post-dose, with additional samples
collected at 15, 30, and 45 minutes after the 6-hour dose in
treatment group C [0825] Days 2-4: before the morning dose at times
24, 48, and 72 hours [0826] Days 5-7: just prior to the 96-hour
dose (day 5) and at 15, 30, and 45 minutes after the dose at hour
96, and at hours 97, 98, 99, 100, 102, 103, 104, 106, 108, 112, 120
(day 6), 132, and 144 (day 7); additional samples were collected at
15, 30, and 45 minutes after the dose at 102 hours for treatment
group C
[0827] FIG. 73 provides a simulation of plasma concentrations over
6 days (144 h) with multiple dosing of CR OC/APAP (administered q12
h) and IR OC/APAP (administered q6 h).
[0828] PK parameters for oxycodone and APAP were calculated using
standard non-compartmental methods. Adverse events were monitored
throughout the study. Analysis of variance (ANOVA) was performed to
compare treatment conditions A, B, and C using the natural
log-transformed, dose-normalized (plasma concentration divided by
dose) PK parameters at steady state (C.sub.maxss, C.sub.minss,
C.sub.ass, and AUC.sub.0-12hss [mean exposure within 0-12 h after
the hour 96 dose on day 5, at steady state]) or natural
log-transformed PK parameters (degree of fluctuation around the
average plasma concentration at steady state, defined as
[C.sub.maxss-C.sub.minss]/C.sub.avss). Geometric least-squares (LS)
means, percent ratio of the geometric LS means, and the
corresponding 90% confidence intervals (CI) for the ratios of the
geometric LS means were calculated for treatment comparisons. A 90%
CI of the geometric LS means ratio fully contained within 80% to
125% indicated no difference between treatments. ANOVA was
performed to analyze the untransformed PK parameter (K.sub.el and
t.sub.1/2). Wilcoxon signed-rank test was utilized to compare
untransformed time with maximum observed plasma concentration at
steady state (T.sub.maxss) between treatments. P.ltoreq.0.05 was
considered a significant difference between treatments.
[0829] FIG. 74 presents the mean steady-state plasma concentration
of oxycodone following the last dose of CR OC/APAP. Steady state
for oxycodone with CR OC/APAP (2 tablets) was reached by day 3; the
oxycodone C.sub.min on days 2 to 4 was >10 ng/mL for the
2-tablet dosage. The estimated oxycodone PK parameters on day 5
while at steady state are presented in Table 83. Steady-state
results for oxycodone with CR OC/APAP (2 tablets) and IR OC/APAP
indicated comparable AUC.sub.0-12hss, C.sub.avss, and C.sub.minss;
however, C.sub.maxss, swing, and degree of fluctuation were 16%,
24%, and 23% lower for CR OC/APAP, respectively. Bioavailability of
CR OC/APAP (2 tablets) was similar to that for IR OC/APAP as
demonstrated by the similar AUC values; however, CR OC/APAP
exhibited less fluctuation in plasma concentrations over time.
Steady-state PK assessments for oxycodone (dose-normalized) showed
no difference relative to AUC.sub.0-12hss, C.sub.maxss,
C.sub.minss, C.sub.avss, and degree of fluctuation between 1 and 2
tablets of CR OC/APAP. Dose proportionality with respect to
oxycodone AUC (LS means ratio of the comparison=97.97%) and
C.sub.max (LS means ratio of the comparison=98.99%) was seen
between 1 and 2 tablets of CR OC/APAP; the 90% CIs of the LS means
ratios for 1 versus 2 tablets were fully contained within the
predefined no-difference range of 80% to 125% for oxycodone.
TABLE-US-00097 TABLE 83 Steady-State (Day 5) Pharmacokinetic
Estimates for Oxycodone (n = 33) CR OC/APAP CR OC/APAP IR OC/APAP
(1 tablet q12h; (2 tablets q12h; (1 tablet q6h; Parameter, mean
(SD) 7.5 mg/325 mg) 15 mg/650 mg) 15 mg/650 mg) AUC.sub.0-12hss, ng
h/mL.sup.a 102.36 (29.30) 208.59 (59.28) 208.93 (57.30) C.sub.avss,
ng/mL 8.53 (2.44) 17.38 (4.94) 17.41 (4.78) C.sub.maxss, ng/mL
12.67 (3.48) 25.67 (7.49) 30.50 (8.91) C.sub.minss, ng/mL 4.06
(1.40) 8.98 (3.52) 8.78 (3.17) Degree of fluctuation, % 101.72
(14.14) 97.17 (18.80) 126.83 (27.93) Swing 2.23 (0.64) 2.03 (0.70)
2.67 (0.92) T.sub.maxss, h.sup.b 2.00 (0.50-10.00) 2.00 (0.50-7.00)
6.50 (0.50-8.02) t.sub.1/2, h 5.46 (1.24) 6.11 (1.46) 5.47 (1.70)
K.sub.el, L/h 0.1326 (0.0269) 0.1199 (0.0291) 0.1387 (0.0418)
.sup.aMean exposure within 0 to 12 hours after the hour 96 dose
(day 5, at steady state) .sup.bMedian (range)
[0830] FIG. 75 presents the mean steady-state plasma concentration
of APAP following the last dose of CR OC/APAP. The estimated PK
parameters for APAP on day 5 while at steady state are presented in
Table 84. Steady state with respect to APAP was reached on day 2 (2
tablets) and day 4 (1 tablet) of CR OC/APAP. On day 5, 7 to 12
hours after the last dose of CR OC/APAP (2 tablets), APAP plasma
levels tapered off to levels below those observed after an
equivalent dose of IR OC/APAP administered every 6 hours.
Steady-state PK assessments for APAP (dose normalized) showed no
difference between any of the 3 treatment arms for AUC.sub.0-12hss,
C.sub.maxss, C.sub.minss, C.sub.avss, and degree of fluctuation.
These results demonstrate that bioavailability of CR OC/APAP is
similar to that for IR OC/APAP. Furthermore, these results
demonstrate dose proportionality with respect to APAP with CR
OC/APAP (both 1 and 2 tablets).
TABLE-US-00098 TABLE 84 Steady-State (Day 5) Pharmacokinetic
Estimates for Acetaminophen (n = 33) CR OC/APAP CR OC/APAP IR
OC/APAP (1 tablet q12h; (2 tablets q12h; (1 tablet q6h; Parameter,
mean (SD) 7.5 mg/325 mg) 15 mg/650 mg) 15 mg/650 mg)
AUC.sub.0-12hss, ng h/mL.sup.a 15307 (4092) 28512 (7714) 28719
(7023) C.sub.avss, ng/mL 1276 (341) 2376 (643) 2393 (585)
C.sub.maxss, ng/mL 3117 (840) 5872 (1932) 5968 (1639) C.sub.minss,
ng/mL 474.67 (163) 870.42 (336) 922.58 (321) Degree of fluctuation,
% 212.08 (52.29) 218.06 (81.14) 213.79 (50.53) Swing 5.95 (2.04)
6.63 (3.61) 5.94 (2.24) T.sub.maxss, h.sup.b 0.50 (0.25-3.00) 0.50
(0.25-3.02) 0.50 (0.25-8.02) t.sub.1/2, h 5.60 (1.35) 7.47 (2.89)
5.74 (2.98) K.sub.el, L/h 0.1308 (0.0317) 0.1026 (0.0292) 0.1416
(0.0515) .sup.aMean exposure within 0 to 12 hours after the hour 96
dose (day 5, at steady state) .sup.bMedian (range)
[0831] Table 85 presents a summary of the most frequently occurring
treatment-emergent adverse events (TEAEs). Overall, 42 subjects
(87.5%) reported .gtoreq.1 TEAE; 67% were considered by the
investigator to be mild in intensity and 21% were considered to be
moderate in intensity. There were no serious TEAEs. The most
frequently reported TEAEs overall were nausea, pruritus, headache,
and dizziness. Fewer subjects receiving 1 tablet of CR OC/APAP
(47.5%) experienced TEAEs than subjects receiving 2 tablets of CR
OC/APAP (70.7%) and IR OC/APAP (73.2%). Ten participants
discontinued because of vomiting (1 tablet of CR OC/APAP, n=1; 2
tablets of CR OC/APAP, n=5; and 1 tablet of IR OC/APAP, n=4) per
protocol specification. Most individual hematology and serum
chemistry values were within the normal range. All changes outside
the reference range were considered by the investigator to not be
clinically significant except for the hematology results from 1
subject (2%) indicating anemia (not considered related to study
medication). There were no significant differences in tolerability
between the 2-tablet treatment with CR OC/APAP and IR OC/APAP.
TABLE-US-00099 TABLE 85 Summary of Most Frequently Occurring
Treatment Emergent Adverse Events CR OC/APAP CR OC/APAP IR OC/APAP
Treatment-Emergent (1 tablet q12h; (2 tablets q12h; (1 tablet q6h;
Adverse Event, 7.5 mg/325 mg) 15 mg/650 mg) 15 mg/650 mg) Overall n
(%) (n = 40) (n = 41) (n = 41) (N = 48) Any TEAE 19 (47.5) 29
(70.7) 30 (73.2) 42 (87.5) Nausea 5 (12.5) 12 (29.3) 13 (31.7) 22
(45.8) Pruritus 5 (12.5) 10 (24.4) 10 (24.4) 18 (37.5) Headache 9
(22.5) 4 (9.8) 7 (17.1) 16 (33.3) Dizziness 5 (12.5) 6 (14.6) 7
(17.1) 15 (31.3) Vomiting 1 (2.5) 5 (12.2) 4 (9.8) 10 (20.8)
Infrequent bowel 4 (10.0) 5 (12.2) 3 (7.3) 10 (20.8) movements
Somnolence 5 (12.5) 5 (12.2) 1 (2.4) 8 (16.7)
[0832] The results of this study demonstrate that both oxycodone
and APAP plasma concentrations rose quickly (T.sub.max at 2 hours
and 30 minutes, respectively) after administration of CR OC/APAP,
and then APAP concentrations tapered off more rapidly than
oxycodone concentrations over the 12-hour dosing interval. At
steady state, the PK profile of CR OC/APAP administered every 12
hours demonstrated: lower peak concentrations and 23% lower degree
of fluctuation in the concentration of oxycodone than with IR
OC/APAP; dose proportionality was demonstrated between the 1- and
2-tablet dosages of CR OC/APAP; comparable bioavailability of
oxycodone and APAP with that of IR OC/APAP administered every 6
hours. CR OC/APAP was generally well tolerated. TEAEs for CR
OC/APAP were typical for those of a low-dose opioid, and similar to
those of IR OC/APAP at equivalent doses. The consistent PK profile
and safety findings support a 12-hour dosing interval for CR
OC/APAP for at least 4.5 days.
Example 37
Comparison of the Pharmacokinetic Profile of Oral,
Controlled-Release Formulation of Oxycodone/Acetaminophen (CR
OC/APAP) Analgesic at Steady State Versus Marketed
Immediate-Release Tablets
[0833] A single-center, randomized, open-label, multiple
comparator, multiple-dose study was conducted to evaluate the
steady-state PK characteristics as well as safety and tolerability
of CR OC/APAP (administered as 2 tablets every 12 hours) compared
with those of commercially-available IR oxycodone, IR
tramadol/APAP, and IR OC/APAP (administered every 6 hours) in
healthy participants. Participants in the study were healthy adults
aged 18 to 55 years, with weight .gtoreq.130 lb and body mass index
of .gtoreq.19 to <30 kg/m.sup.2. Current recreational drug users
were excluded, as were subjects with a history of abuse/addiction
or recent illicit drug use (within 2 years) or nicotine use (within
6 months). Other exclusion criteria included a history of any
condition that might interfere with the absorption, distribution,
metabolism, or excretion of study drug; or history of gastric
bypass or gastric band surgery. A total of 48 adults were enrolled,
and 24 (50.0%) completed all treatment periods and were included in
the PK analysis.
[0834] Participants were randomly assigned to receive each study
medication in 1 of 4 treatment sequences (4 periods, .about.7 days
each) separated by a minimum of 13 days. The following treatments
were administered under fasted conditions. [0835] CR OC/APAP 7.5
mg/325 mg (see selected example from Chart No. 1); 2 tablets (total
dose, 15 mg/650 mg) every 12 hours for 4.5 days [0836] IR oxycodone
(commercially-available) 15 mg; 1 tablet every 6 hours for 4.5 days
[0837] IR tramadol/APAP (commercially-available) 37.5 mg/325 mg; 1
tablet every 6 hours for 4.5 days [0838] IR OC/APAP
(commercially-available) 7.5 mg/325 mg; 1 tablet every 6 hours for
4.5 days
[0839] For participants who completed all treatment periods, the PK
of oxycodone was compared among CR OC/APAP, IR oxycodone, and IR
OC/APAP, and the PK of APAP was compared among CR OC/APAP, IR
tramadol/APAP, and IR OC/APAP. Blood samples for bioanalysis of
oxycodone and APAP were collected predose and at 30 minutes and 1,
2, 3, 4, 6, 6.5, 8, and 12 hours after dosing on day 1; before the
morning dose on days 2 through 4; predose on day 5 (96 hours); and
at 96.5, 97, 98, 99, 100, 102, 102.5, 104, 108, 120 (day 6), and
132 hours.
[0840] Oxycodone and APAP concentrations were determined using
liquid chromatography/tandem mass spectrometry. Plasma
concentration versus time data were used to estimate the PK
parameters of oxycodone and APAP, calculated using standard
non-compartmental methods. For steady-state data (day 5), analysis
of variance was performed to compare treatments using the natural
log-transformed, dose-normalized (plasma concentration divided by
dose administered) PK parameters (C.sub.maxss, C.sub.minss,
C.sub.avgss, and AUC.sub.0-12ss) or natural log-transformed PK
parameters (degree of fluctuation of the plasma concentration
[100(C.sub.maxss-C.sub.minss)/C.sub.avgss] and swing of plasma
concentrations, defined as [(C.sub.maxs-C.sub.minss)/C.sub.minss])
as the dependent variable, with sequence, treatment, and period as
fixed effects and subject nested within sequences as random effect.
Dose normalization was utilized to compare concentration across
different dosage strengths. Geometric least-squares (LS) means,
percent ratio of the geometric LS means, and the corresponding 90%
confidence interval (CI) of the geometric LS means were calculated
for treatment comparisons. 90% CI of the geometric LS means ratio
fully contained within 80% to 125% concluded no difference between
treatments. Wilcoxon signed-rank test was utilized to compare
untransformed time to maximum observed plasma concentration at
steady state (T.sub.maxss) between treatments. P.ltoreq.0.05 was
considered a significant difference between treatments. Summary
statistics were compiled for treatment-emergent adverse events
(TEAEs).
[0841] FIG. 76 presents the steady-state (day 5) mean oxycodone
plasma concentration over time for the study completers (n=24).
Steady state for oxycodone was attained at day 2 (24 h) after
initial CR OC/APAP administration, and the oxycodone C.sub.min on
days 2 to 4 was >11 ng/mL. Mean plasma oxycodone concentrations
increased rapidly after CR OC/APAP administration and were
approximately 37% of the peak plasma concentration 12 hours after
dosing. The estimated oxycodone PK parameters on day 5 (steady
state) are presented in Table 86. Dose-normalized AUC.sub.0-12hss,
C.sub.avgss, C.sub.maxss, and C.sub.minss of oxycodone were
comparable across groups (90% CIs for the treatment comparisons
were fully contained within the predefined no-difference range of
80%-125%). Dose-normalized mean degree of fluctuation of oxycodone
was 84% for CR OC/APAP during the dosing interval (q12 h) and was
111% for IR OC/APAP (q6 h); CR OC/APAP demonstrated a 23% lower
degree of fluctuation than IR OC/APAP. Dose-normalized swing of
oxycodone from CR OC/APAP was 1.65, 31% higher than that from IR
oxycodone (1.32) but 20% lower than that from IR OC/APAP (2.13).
The elimination half-life (t.sub.1/2) for oxycodone from CR OC/APAP
was approximately 1 hour longer than IR oxycodone and IR
OC/APAP.
TABLE-US-00100 TABLE 86 Steady-State (Day 5) Pharmacokinetic
Estimates for Oxycodone (n = 24) Parameter, mean (SD) CR OC/APAP IR
OC/APAP IR Oxycodone AUC.sub.0-12hss, ng h/mL 208.34 (45.34) 191.54
(42.81) 376.88 (83.90) C.sub.avss, ng/mL 17.36 (3.78) 15.96 (3.57)
31.41 (6.99) C.sub.maxss, ng/mL 24.00 (5.38) 26.32 (6.18) 45.15
(10.54) C.sub.minss, ng/mL 9.31 (2.39) 8.81 (2.40) 19.91 (4.93)
Degree of fluctuation, % 83.89 (17.58) 110.90 (33.39) 79.94 (19.83)
Swing 1.65 (0.58) 2.13 (0.94) 1.32 (0.50) T.sub.maxss, h.sup.a 3.00
(1.00-5.92) 7.25 (0.50-8.13) 3.00 (1.00-12.00) K.sub.el, L/h 0.1318
(0.0223) 0.1517 (0.0205) 0.1525 (0.0206) t.sub.1/2, h 5.40 (0.87)
4.65 (0.62) 4.62 (0.59) .sup.aMedian (range)
[0842] FIG. 77 presents the steady-state (day 5) mean APAP plasma
concentration over time for the study completers (n=24). The
estimated PK parameters for APAP on day 5 while at steady state are
presented in Table 87. Steady state for APAP was attained by day 2
(24 h) after initial CR OC/APAP administration. On day 5, mean
plasma concentrations of APAP increased rapidly after
administration of CR OC/APAP, but declined to 17% of peak
concentration (C.sub.maxss) by 12 hours after dosing. Mean plasma
concentrations of APAP from CR OC/APAP were less than those from IR
tramadol/APAP and IR OC/APAP approximately 7 hours after dosing on
day 5. Dose-normalized AUC.sub.0-12hss, C.sub.avgss, C.sub.maxss,
and degree of fluctuation were comparable across treatments.
Dose-normalized C.sub.minss after CR OC/APAP was 21% lower than IR
tramadol/APAP and 22% lower than IR OC/APAP. The t.sub.1/2 of APAP
from CR OC/APAP (LS mean=8.3 h) was similar to IR OC/APAP (LS
mean=7.8 h), and approximately 2.31 hours longer compared with IR
tramadol/APAP (LS mean=5.98 h).
TABLE-US-00101 TABLE 87 Steady-State (Day 5) Pharmacokinetic
Estimates for APAP (n = 24) Parameter, mean (SD) CR OC/APAP IR
OC/APAP IR Tramadol/APAP AUC.sub.0-12hss, ng h/mL 28160.40
(5807.09) 29284.22 (5477.73) 29711.92 (5427.37) C.sub.avss, ng/mL
2346.70 (483.92) 2440.35 (456.48) 2475.99 (452.28) C.sub.maxss,
ng/mL 4792.50 (1132.40) 4876.67 (1383.08) 5078.33 (1189.70)
C.sub.minss, ng/mL 852.75 (273.25) 1069.13 (291.83) 1070.92
(367.35) Degree of 169.13 (39.83) 155.25 (38.77) 163.90 (47.17)
fluctuation, % Swing 5.08 (2.07) 3.81 (1.63) 4.22 (2.14)
T.sub.maxss, h.sup.a 1.00 (0.50-4.00) 0.75 (0.25-8.00) 0.88
(0.25-8.00) K.sub.el, L/h 0.1072 (0.0285) 0.1201 (0.0338) 0.1355
(0.0279) t.sub.1/2, h 6.90 (1.76) 6.21 (1.79) 5.32 (1.10)
.sup.aMedian (range)
[0843] Standard safety assessments including adverse event
monitoring and clinical laboratory tests were performed throughout
the study. Overall, 44 of 48 (91.7%) enrolled participants reported
.gtoreq.1 TEAE; all were rated by the investigator to be mild or
moderate in severity; there were no serious or severe TEAEs. As
shown in Table 88, the most frequently occurring TEAEs were nausea,
vomiting, dizziness, pruritus, and headache. More subjects reported
TEAEs with IR oxycodone administration (82.4%) than with IR OC/APAP
(64.5%), CR OC/APAP (45.5%), or IR tramadol/APAP (42.9%).
Gastrointestinal TEAEs were reported for 50.0%, 35.5%, 30.3%, and
14.3% during IR oxycodone, IR OC/APAP, CR OC/APAP, and IR
tramadol/APAP administration, respectively. 22 (45.8%) subjects
were withdrawn from the study due to vomiting (as required by the
protocol); 7 (21.2%) during CR OC/APAP treatment. No apparent
clinically significant treatment-related trends were observed in
clinical laboratory assessments or physical examination
findings.
TABLE-US-00102 TABLE 88 Most Frequently Occurring (>20% in the
Overall Group) TEAEs IR IR CR Oxy- Tramadol/ IR TEAE, OC/APAP
codone APA OC/APAP Overall n (%) (n = 33) (n = 34) P (n = 28) (n =
31) (N = 48) Any TEAE 15 (45.5) 28 (82.4) 12 (42.9) 20 (64.5) 44
(91.7) Nausea 8 (24.2) 13 (38.2) 2 (7.1) 9 (29.0) 26 (54.2)
Vomiting 7 (21.2) 8 (23.5) 2 (7.1) 5 (16.1) 22 (45.8) Dizziness 4
(12.1) 13 (38.2) 2 (7.1) 4 (12.9) 19 (39.6) Pruritus 7 (21.2) 13
(38.2) 5 (17.9) 2 (6.5) 19 (39.6) Headache 5 (15.2) 5 (14.7) 3
(10.7) 3 (9.7) 14 (29.2)
[0844] The results of this study demonstrate that steady state was
achieved by day 2 (24 h) of CR OC/APAP initiation for both
oxycodone and APAP. Both oxycodone and APAP plasma concentrations
rose quickly after administration of CR OC/APAP, with a shorter
T.sub.max for APAP (1 h) than for oxycodone (3 h). At steady state,
CR OC/APAP (2 tablets every 12 hours) produced a comparable PK
profile to IR products dosed every 6 hours, with less fluctuation
in oxycodone concentrations compared with IR OC/APAP and lower
trough plasma concentrations of APAP compared with both IR
comparators prior to subsequent dosing. CR OC/APAP was generally
well tolerated; the most frequently reported TEAEs were nausea,
vomiting, and pruritus. TEAEs were similar to IR products
containing oxycodone. These findings support the safe and
appropriate administration of CR OC/APAP during a dosing interval
of every 12 hours.
Example 38
Comparison of the Pharmacokinetic Profile of a Single Dose of a
Controlled-Release Oxycodone and Acetaminophen Combination Tablet
(CR OC/APAP) and Marketed Immediate-Release Opioids and
Opioid/Acetaminophen Combination Tablets
[0845] A single-center, randomized, open-label, single-dose study
was conducted to evaluate the single-dose pharmacokinetic (PK)
characteristics, safety, and tolerability of CR OC/APAP every 12
hours for a single dose (administered once) compared with those of
commercially-available forms of IR oxycodone, IR tramadol/APAP, and
IR OC/APAP every 6 hours for 2 doses in healthy participants.
Participants in the study were healthy adults aged 18 to 55 years,
with a weight .gtoreq.130 lb and a body mass index of .gtoreq.19 to
<30 kg/m.sup.2. Current recreational drug users were excluded,
as were subjects with a history of abuse/addiction or recent
illicit drug use (within 2 years) or nicotine use (within 6
months). Other exclusion criteria included a history of any
condition that might interfere with the absorption, distribution,
metabolism, or excretion of study drug; or history of gastric
bypass or gastric band surgery. A total of 48 adults were enrolled;
30 (62.5%) completed all treatment periods. Data from 29 subjects
who completed all 4 study periods were included in the PK analyses;
data from 1 completer were excluded due to a protocol violation
(consumed prohibited medications).
[0846] Participants were randomly assigned to receive each study
medication in 1 of 4 treatment periods (.about.48 h each) separated
by a minimum of 7 days. The following treatments were administered
under fasted conditions: [0847] CR OC/APAP (OC/APAP) 7.5 mg/325 mg
(see selected example from Chart No. 1); 2 tablets (total dose, 15
mg/650 mg) administered once
[0848] IR oxycodone (commercially-available) 15 mg; 1 tablet every
6 hours for 2 doses [0849] IR tramadol/APAP
(commercially-available) 37.5 mg/325 mg; 1 tablet every 6 hours for
2 doses [0850] IR OC/APAP (commercially-available) 7.5 mg/325 mg; 1
tablet every 6 hours for 2 doses
[0851] Subjects who completed all 4 treatment periods of the study
were included in PK analyses. The PK of oxycodone was compared
among CR OC/APAP, IR oxycodone, and IR OC/APAP. The PK of APAP was
compared among CR OC/APAP, IR tramadol/APAP, and IR OC/APAP. Blood
samples for bioanalysis of oxycodone and APAP were collected
predose (<1 h prior to dosing), and at 15, 30, and 45 minutes
and 1, 2, 3, 4, 6, 6.5, 7, 8, 9, 10, 12, 16, 18, 20, 24, and 36
hours after dosing. Oxycodone and APAP concentrations were
determined using liquid chromatography/tandem mass spectrometry.
Plasma concentration versus time data were used to estimate the PK
parameters of oxycodone and APAP, calculated using standard
non-compartmental methods. An analysis of variance was performed to
compare treatments using the natural log-transformed
dose-normalized (plasma concentration divided by dose) PK
parameters (AUC.sub.0-t, AUC.sub.0-inf, and C.sub.max) or the
nontransformed PK parameters (K.sub.el and t.sub.1/2) as the
dependent variables with sequence, treatment, and period as fixed
effects and subjects nested within sequences as random effect.
Geometric least-squares (LS) means, ratio of geometric LS means,
the corresponding 90% confidence interval (CI) for the LS means
ratio, intrasubject variability, and P values for testing the fixed
effects were summarized. A 90% CI of the geometric LS means ratio
fully contained within 80% to 125% concluded no difference between
treatments. Wilcoxon signed-rank test was performed to determine
the statistical significance of the median difference for T.sub.max
and lag time (t.sub.lag). P.ltoreq.0.05 was considered a
significant difference between treatments. Summary statistics were
compiled for treatment-emergent adverse events (TEAEs).
[0852] FIG. 78 presents the mean plasma concentrations of oxycodone
versus time for the three treatments containing oxycodone. Table 89
presents a summary of the plasma PK parameters for oxycodone. As
shown in FIG. 78 and Table 89, mean plasma concentrations of
oxycodone increased rapidly after CR OC/APAP administration. Lag
time (t.sub.lag) was 0; median T.sub.max was 4 hours. Oxycodone was
eliminated slowly (mean plasma oxycodone concentrations from CR
OC/APAP were approximately 45% of peak 12 hours after dosing). The
total dose-normalized systemic exposure to oxycodone from a single
dose of CR OC/APAP was comparable to that from 2 doses (q6 h) of
the comparators (IR oxycodone and IR OC/APAP). Peak concentrations
of oxycodone from CR OC/APAP were achieved at 4 hours; time to
C.sub.max for IR oxycodone (8 h; P=0.065) and IR OC/APAP (8 h;
P=0.004) occurred approximately 2 hours after the second dose.
Oxycodone C.sub.max with CR OC/APAP (dose-normalized) was
equivalent to C.sub.max achieved with IR oxycodone, but 27% lower
than that with IR OC/APAP.
TABLE-US-00103 TABLE 89 Plasma Pharmacokinetic Parameters for
Oxycodone (n = 29) Parameter, mean (SD) CR OC/APAP.sup.a IR
OC/APAP.sup.a IR Oxycodone.sup.b AUC.sub.0-t, ng h/mL 167.90
(36.83) 169.85 (34.23) 334.61 (62.46) AUC.sub.0-inf, ng h/mL 169.34
(37.03) 171.53 (34.05) 336.30 (62.77) C.sub.max, ng/mL 14.28 (2.94)
19.42 (4.62) 31.27 (8.17) T.sub.max, h.sup.c 4.00 (0.75-12.00)
8.00.sup.d (0.50-12.00) 8.00.sup.d (0.75-12.00) T.sub.lag, h.sup.c
0.00 (0.00-0.25) 0.00 (0.00-0.25) 0.00 (0.00-0.27) K.sub.el,
h.sup.-1 0.1577 (0.0223) 0.1764 (0.0226) 0.1796 (0.0141) t.sub.1/2,
h 4.47 (0.58) 3.99 (0.48) 3.88 (0.31) .sup.a15 mg oxycodone
.sup.b30 mg oxycodone .sup.cMedian (range) .sup.d2 hours after
second dose
[0853] FIG. 79 presents the mean plasma concentrations of APAP
versus time for the three treatments containing APAP. Table 90
presents a summary of the plasma PK parameters for APAP. As shown
in FIG. 79 and Table 90, mean plasma concentrations of APAP
increased rapidly after CR OC/APAP administration. Mean plasma APAP
levels from CR OC/APAP were only 18% of peak by 12 hours after
dosing. APAP plasma concentrations for CR OC/APAP fell below the
levels for the comparators by 8 hours after dosing (2 hours after
the second dose of the comparator). The total dose-normalized
systemic exposure (AUC.sub.0-t and AUC.sub.0-inf) to APAP from a
single dose of CR OC/APAP was comparable to that from 2 doses (q6
h) of the comparators (IR tramadol/APAP and IR OC/APAP). The 90%
CIs of the ratios of geometric LS means for AUC.sub.0-t and
AUC.sub.0-inf were fully contained within the predefined
no-difference range of 80% to 125%. Dose-normalized peak
concentrations of APAP were equivalent, but were achieved more
rapidly with CR OC/APAP than with IR tramadol/APAP
(P<0.001).
TABLE-US-00104 TABLE 90 Plasma Pharmacokinetic Parameters for APAP
(n = 29) Parameter, mean (SD) CR OC/APAP.sup.a IR OC/APAP.sup.a IR
Tramadol/APAP.sup.a AUC.sub.0-t, ng h/mL 29064.91 (6851.20)
29192.56 (6892.03) 29934.67 (6577.90) AUC.sub.0-t, ng h/mL 30759.04
(7000.49) 30367.98 (7290.82) 30989.26 (6759.41) C.sub.max, ng/mL
4653.79 (1360.28) 4387.24 (1326.26) 4255.52 (1004.33) T.sub.max,
h.sup.b 0.75 (0.50-2.00) 0.75 (0.25-12.00) 2.00 (0.50-9.00)
T.sub.lag, h.sup.b 0.00 (0.00-0.25) 0.00 (0.00-0.25) 0.00
(0.00-0.50) K.sub.el, h.sup.-1 0.1328 (0.0375) 0.1684 (0.0435)
0.1780 (0.0399) t.sub.1/2, h 5.75 (2.07) 4.41 (1.24) 4.12 (1.08)
.sup.aTotal dose of 650 mg APAP .sup.bMedian (range)
[0854] Standard safety assessments including adverse event
monitoring and clinical laboratory tests (bilirubin and other liver
function tests, and serum chemistry, hematology, and urinalysis
measures) were performed throughout the study. Table 91 presents a
summary of the most frequently occurring TEAEs. Overall, 29 of 48
(60.4%) enrolled participants reported TEAE. The most common TEAEs
after CR OC/APAP administration were nausea, dizziness, and
somnolence. More subjects reported TEAEs after receiving IR
oxycodone (58.1%) than after receiving IR OC/APAP (37.5%), CR
OC/APAP (23.1%), or IR tramadol/APAP (22.2%). All TEAEs were rated
by the investigator as either mild or moderate in severity; there
were no serious or severe TEAEs. 13 subjects (27.1%) were withdrawn
from the study due to vomiting (as required by the protocol); 10
subjects (23.3%) during IR oxycodone treatment and 1 each during
treatment with CR OC/APAP (2.6%), IR tramadol/APAP (2.8%), and IR
OC/APAP (2.5%). No clinically significant treatment-related trends
were observed in clinical laboratory assessments (including
bilirubin and other liver function tests) or physical examination
findings.
TABLE-US-00105 TABLE 91 Most Frequently Occurring (>10% in the
Overall Group) TEAEs CR IR IR IR TEAE, OC/APAP.sup.a
Oxycodone.sup.b Tramadol/APAP.sup.c OC/APAP.sup.d Overall n (%) (n
= 39) (n = 43) (n = 36) (n = 40) (N = 48) Any TEAE 9 (23.1) 25
(58.1) 8 (22.2) 15 (37.5) 29 (60.4) Nausea 5 (12.8) 15 (34.9) 3
(8.3) 9 (22.5) 21 (43.8) Dizziness 3 (7.7) 10 (23.3) 2 (5.6) 4
(10.0) 16 (33.3) Vomiting 1 (2.6) 10 (23.3) 1 (2.8) 1 (2.5) 13
(27.1) Headache 1 (2.6) 5 (11.6) 3 (8.3) 3 (7.5) 10 (20.8)
Somnolence 3 (7.7) 2 (4.7) 0 (0.0) 3 (7.5) 5 (10.4) Feeling hot 1
(2.6) 2 (4.7) 0 (0.0) 2 (5.0) 5 (10.4) Pruritus 1 (2.6) 5 (11.6) 0
(0.0) 1 (2.5) 5 (10.4) .sup.a2 tablets once; 15 mg OC/650 mg APAP
total .sup.b1 tablet q6h; 30 mg OC total .sup.c1 tablet q6h; 75 mg
tramadol/650 mg APAP total .sup.d1 tablet q6h; 15 mg OC/650 mg APAP
total
[0855] The results of this study demonstrate that plasma oxycodone
and APAP levels rose rapidly after a single dose of CR OC/APAP.
Plasma oxycodone concentrations were sustained throughout the
proposed dosing interval (12 hours); however, APAP concentrations
slowly declined to 18% of the peak at 12 hours. The low APAP plasma
concentrations at 12 hours suggest little accumulation of APAP
after repeated dosing of CR OC/APAP. The similarity of the relevant
PK parameters to the IR marketed compounds supports a dosing
interval of CR OC/APAP as used in this study. CR OC/APAP was
generally well tolerated; the most frequently reported TEAEs were
nausea, dizziness, and somnolence. These findings support a 12-hour
dosing interval of CR OC/APAP for patients with moderate to severe
acute pain.
Example 39
Half-Value Duration Analysis for Acetaminophen after Single and
Multiple Doses of Oral Controlled-Release Oxycodone/Acetaminophen
(CR OC/APAP) Tablets
[0856] Post hoc analysis of PK data from two randomized,
open-label, crossover studies (1 single dose and 1 multiple dose)
was performed to evaluate the half-value duration (HVD) for APAP
after single and multiple doses (administered q12 h) of CR OC/APAP
(2 tablets; total, 15 mg OC/650 mg APAP) (see selected example from
Chart No. 1) compared with commercially-available IR OC/APAP (1
tablet; 7.5 mg/325 mg) administered every 6 hours. Participants
were healthy adults aged 18 to 55 years, with weight 130 lb and a
body mass index of 19 to <30 kg/m.sup.2. Exclusion criteria
included: current recreational drug use; history of abuse/addiction
or recent illicit drug use (within 2 years) or nicotine use (within
6 months); history of any condition that may interfere with the
absorption, distribution, metabolism, or excretion of study
medication; or history of gastric bypass or gastric band surgery.
PK data were analyzed for 29 subjects in the single-dose study and
24 subjects in the multiple-dose study; data from 1 participant in
the single-dose study were excluded due to the use of prohibited
medication (APAP).
[0857] The following treatments were administered under fasted
conditions: [0858] Oral doses of CR OC/APAP (7.5 mg OC/325 mg APAP)
(see selected example from Chart No. 1) administered as 2 tablets
(total dose, 15 mg/650 mg) taken once (single-dose study) or 2
tablets taken twice daily every 12 hours over 4.5 days for 9 doses
(multiple-dose study) [0859] Oral doses of IR OC/APAP (commercially
available) 7.5 mg/325 mg administered during a separate trial
period as 1 tablet every 6 hours for 2 doses (single-dose study) or
1 tablet every 6 hours over 4.5 days for 18 doses (multiple-dose
study)
[0860] Blood samples for bioanalysis of APAP were collected up to
36 hours after dosing in the single-dose study and up to 132 hours
after the hour-0 dose in the multiple-dose study. HVD, degree of
fluctuation (100[C.sub.maxss-C.sub.minss]/C.sub.avgss), C.sub.max,
T.sub.max, and area under the concentration-time curve (AUC) were
calculated for APAP. Descriptive statistics were used to report
demographics and baseline characteristics. For the multiple-dose
study, analyses were performed for both the initial dose period
(day 1, 0-12 h) and at steady state (day 5, 0- to 12-h dosing
interval; i.e., 96-108 h). PK analyses included subjects who
completed each study. Mean concentration-time profiles were
presented on a linear scale. Individual plasma concentration versus
actual time data were used to estimate the PK parameters of APAP.
HVD of APAP after CR OC/APAP (single or multiple dose) was compared
with that after IR OC/APAP using paired 2-tailed t tests.
Descriptive statistics and paired t tests were calculated for the
percentage difference in HVD relative to the IR product (% RDHVD);
% RDHVD was calculated as the average percentage difference in HVD
for CR OC/APAP relative to IR OC/APAP for individual subjects.
[0861] FIGS. 80 and 81 present the plasma APAP concentration over
time and HVD for APAP in the initial 12 hours after dosing for the
single-dose and multi-dose studies, respectively. FIG. 80 presents
the single-dose study results. FIG. 81 presents the multi-dose
study results. Table 92 presents the PK measures for APAP in the
initial 12 hours after dosing for both the single-dose and
multi-dose studies. As shown in FIGS. 80 and 81 and in Table 92,
HVD of APAP was not significantly different for CR OC/APAP and IR
OC/APAP after the first administration (difference of 0.73 h
[P=0.133] in the single-dose study, and 0.27 h [P=0.520] on day 1
in the multiple-dose study). AUC and C.sub.max for APAP were
similar after administration of CR OC/APAP and IR OC/APAP.
TABLE-US-00106 TABLE 92 Pharmacokinetic Measures for APAP, Initial
12 Hours After Dosing Parameter, Single-Dose Study Multiple-Dose
Study, Day 1 mean (SD) CR OC/APAP IR OC/APAP CR OC/APAP IR OC/APAP
C.sub.max, ng/mL 4653.79 (1360.3) 4387.24 (1326.3) 4857.5 (1066.5)
4317.92 (1006.3) T.sub.max, h.sup.a 0.75 (0.5-2.0) 0.75 (0.25-12.0)
1.00 (0.5-4.0) 0.53 (0.5-8.0) AUC, ng h/mL 30759.0 (7000.5).sup.b
30368.0 (7290.8).sup.b 24924.3 (5667.5).sup.c 25093.7
(5085.0).sup.c HVD, h 3.68 (1.8) 4.41 (2.3) 3.33 (1.5) 3.60 (2.0)
.sup.aMedian (range) .sup.bAUC.sub.0-inf .sup.cAUC.sub.0-12 h
[0862] FIG. 82 presents the steady-state plasma APAP concentration
over time and HVD for APAP during day 5 of the multi-dose study.
Table 93 presents the steady-state (day 5) PK measures for APAP.
Steady state APAP concentrations were reached within 2 days (24 h
after first dose) for CR OC/APAP and at 1 day (12 h) for IR
OC/APAP. At day 5 under steady-state conditions, the HVD of APAP
after administration of CR OC/APAP was significantly greater than
that after administration of IR OC/APAP (difference of 1.13 h
[P=0.024]). HVD was 106% greater for CR OC/APAP versus IR OC/APAP.
There was no significant difference in degree of fluctuation
between CR OC/APAP and IR OC/APAP. AUC during the first 12 hours
after dosing on day 5 (at steady state), C.sub.max, and T.sub.max
for APAP were similar for CR OC/APAP and IR OC/APAP.
TABLE-US-00107 TABLE 93 Steady-State Pharmacokinetic Measures for
APAP (Day 5) Parameter CR OC/APAP IR OC/APAP C.sub.maxss,
ng/mL.sup.a 4792.50 (1132.4) 4876.67 (1383.1) T.sub.maxss, h.sup.b
1.00 (0.5-4.0) 0.75 (0.25-8.0) AUC.sub.0-12hss, ng h/mL.sup.a 28160
(5807) 29284 (5478) Degree of fluctuation, % 169.13 (39.8) 155.25
(38.8) HVD.sub.ss, h.sup.a 4.24 (1.4) 3.11 (1.8) .sup.aMean (SD)
.sup.bMedian (range)
[0863] Safety and tolerability were monitored throughout each
study. Table 94 presents the most frequently occurring
treatment-emergent adverse events (TEAEs). The most frequently
reported TEAEs following administration of CR OC/APAP were nausea,
vomiting, pruritus, dizziness, and headache.
TABLE-US-00108 TABLE 94 Most Frequently Occurring
Treatment-Emergent Adverse Events (.gtoreq.5% with CR OC/APAP)
Single-Dose Study Multiple-Dose Study IR CR IR CR OC/APAP OC/APAP
OC/APAP OC/APAP TEAE, n (%) (n = 39) (n = 40) (n = 33) (n = 31) Any
TEAE 9 (23.1) 15 (37.5) 15 (45.5) 20 (64.5) Nausea 5 (12.8) 9
(22.5) 8 (24.2) 9 (29.0) Dizziness 3 (7.7) 4 (10.0) 4 (12.1) 4
(12.9) Vomiting 1 (2.6) 1 (2.5) 7 (21.2) 5 (16.1) Headache 1 (2.6)
3 (7.5) 5 (15.2) 3 (9.7) Somnolence 3 (7.7) 3 (7.5) 1 (3.0) 1 (3.2)
Pruritus 1 (2.6) 1 (2.5) 7 (21.2) 2 (6.5) Feeling hot 1 (2.6) 2
(5.0) 2 (6.1) 2 (6.5) Abdominal 1 (2.6) 0 (0.0) 2 (6.1) 3 (9.7)
pain
[0864] The results of this study demonstrate that C.sub.max,
T.sub.max, and AUC of APAP were similar after single-dose
administration as well as after dosing at steady state. HVD for
APAP at steady state was significantly greater for CR OC/APAP
compared with IR OC/APAP. The HVD after initial dosing was similar
between treatments. CR OC/APAP was generally well tolerated, with
TEAEs that were consistent with those associated with opioid
therapy. The results of this PK analysis support the administration
of CR OC/APAP every 12 hours for the management of moderate to
severe acute pain.
Example 40
Relationship Between Oxycodone Pharmacokinetics and Subjective Drug
Effects Following Oral Administration of an Immediate-Release
Combination of Oxycodone and Acetaminophen and Controlled-Release
Oxycodone/Acetaminophen (CR OC/APAP) Tablets
[0865] A single-center, randomized, double-blind, double-dummy,
active- and placebo-controlled, crossover study was conducted to
examine the relationship between oxycodone PK parameters and the
pharmacodynamic (PD) parameters of participant-reported drug
liking, drug high, and good drug effects, which have been
associated with abuse. PK and PD parameters were assessed after
administration of intact and crushed CR OC/APAP (see selected
example from Chart No. 1) and commercially-available IR OC/APAP to
recreational opioid users. Participants included healthy adult
(18-55 y) male and female nondependent, recreational opioid users
who reported occasions of recreational opioid use over the past
year, including .gtoreq.1 occasion within the past 12 weeks.
[0866] Participants initially underwent a naloxone challenge test
to confirm a lack of physical dependence on opioids and a drug
discrimination test to determine that they could detect the
subjective effects of oxycodone. During the drug discrimination
test, all participants received single doses of IR OC/APAP (15
mg/650 mg total; two tablets of 7.5 mg/325 mg each) (see selected
example from Chart No. 1) and placebo and reported on the
subjective effects. Participants who could not discriminate between
active drug and placebo or tolerate this single dose were excluded
from enrollment. The treatment phase included a total of 7
assessment periods, with a 72-hour washout period between doses.
Out of 107 participants who entered the study, were checked into
the clinical facility, and completed the study inclusion phase, 61
participants met inclusion criteria and entered the treatment
phase; of these, 55 completed all 7 assessment periods and were
included in the analysis population. Participants had a mean age of
26 years and approximately 73% were male. Most participants (95%)
had a history of alcohol use, and the majority (67%) had a history
of tobacco use.
[0867] Because of the history of prescription opioid abuse in this
population, IR OC/APAP was encapsulated for proper blinding. To
ensure blinding of all study treatments, participants received
matching placebos for each possible treatment configuration so dose
administration in each treatment period consisted of 8 capsules and
4 tablets. During each assessment period, participants received a
single dose of one of the 7 study treatments:
[0868] CR OC/APAP intact
[0869] High dose: 30 mg/1300 mg (4 tablets)
[0870] Low dose: 15 mg/650 mg (2 tablets)
[0871] IR OC/APAP intact
[0872] High dose: 30 mg/1300 mg (4 tablets, over-encapsulated)
[0873] Low dose: 15 mg/650 mg (2 tablets, over-encapsulated)
[0874] CR OC/APAP crushed (encapsulated)
[0875] High dose: 30 mg/1300 mg (8 capsules)
[0876] IR OC/APAP crushed (encapsulated)
[0877] High dose: 30 mg/1300 mg (4 capsules)
[0878] Placebo
[0879] Plasma was extracted from whole blood samples collected
before dosing and up to 24 hours after each dose. Plasma oxycodone
and APAP concentrations were determined using liquid chromatography
with tandem mass spectrometry detection. Oxycodone and APAP PK
parameters, including C.sub.max, T.sub.max, and area under the
concentration-time curve (AUC) for 0-1 h, 0-2 h, 0-4 h, 0-8 h, 0-12
h, and from hour 0 extrapolated to infinity, were analyzed by
standard non-compartmental methods using WinNonlin.RTM., version
6.1 or higher (Pharsight, Cary, N.C.). Pharmacodynamic (PD) outcome
measures included patient-reported visual analog scale (VAS) scores
for: drug liking--assessed on a 100-mm bipolar VAS (0 mm=Strong
disliking; 50 mm=Neither like or dislike; 100 mm=Strong liking);
drug high--assessed on a 100-mm unipolar VAS (0 mm=None; 100
mm=Extremely); and good drug effects--assessed on a 100-mm unipolar
VAS (0 mm=None; 100 mm=Extremely). PD measures included peak drug
effects (E.sub.max), time to E.sub.max (TE.sub.max), and area under
the drug effect curve (AUE) assessed at multiple time points from
0-12 hours. The relationship between oxycodone PK and PD outcomes
was evaluated by calculating correlation coefficients between these
parameters (e.g., C.sub.max vs E.sub.max and AUC.sub.0-x vs
AUE.sub.0-x) using SAS.RTM. version 9.1 or higher (SAS Institute
Inc., Cary, N.C.).
[0880] Table 95 presents a summary of the oxycodone PK parameters
from this study. Oxycodone C.sub.max following the administration
of high- and low-dose intact CR OC/APAP was approximately half the
value observed with the same doses of IR OC/APAP. Median oxycodone
T.sub.max was significantly longer for intact CR OC/APAP compared
with the same dose of intact IR OC/APAP, representing increases of
185% and 96%, respectively, for low and high doses (P<0.001).
Oxycodone AUC values for the first 4 hours after dosing were also
lower for intact CR OC/APAP than IR OC/APAP; however, overall
oxycodone exposure (AUC.sub.0-t and AUC.sub.0-inf) was equivalent
between formulations. High-dose CR OC/APAP produced oxycodone
C.sub.max levels that were similar for the intact and crushed
formulation. Crushing CR OC/APAP significantly reduced the IR
characteristic. Median T.sub.max for crushed CR OC/APAP was delayed
by 1.5 hours versus intact CR OC/APAP (73% increase). High-dose
intact CR OC/APAP produced oxycodone levels soon after dosing
(e.g., AUC.sub.0-2h) that were considerably greater than those for
crushed CR OC/APAP (36.7 ngh/mL vs 17.3 ngh/mL).
TABLE-US-00109 TABLE 95 Oxycodone Pharmacokinetic Parameters
Low-Dose High-Dose High-Dose OC/APAP OC/APAP OC/APAP (15 mg/650 mg)
(30 mg/1300 mg) (30 mg/1300 mg) PK Intact Intact Crushed Parameters
CR IR CR IR CR IR C.sub.max, ng/mL.sup.a 14.4 34.1 31.4 66.2 32.2
55.1 (3.6) (9.7) (7.6) (24.5) (8.5) (18.7) T.sub.max, h.sup.b 3.08
1.08 2.08 1.06 3.59 1.08 (0.58-6.08) (0.42-4.18) (0.55-6.12)
(0.52-8.15) (1.10-6.10) (0.52-5.17) .sup.aMean (SD) .sup.bMedian
(range)
[0881] FIGS. 83 to 88 present the 12-hour oxycodone plasma
concentrations and PD outcomes for drug liking and drug high. In
general, drug liking, drug high, and good drug effects were greater
for all IR OC/APAP formulations compared with CR OC/APAP. In
addition, crushing CR OC/APAP delayed and did not increase positive
subjective effects and produced similar or less drug liking, drug
high, and good drug effects than the same dose of intact CR OC/APAP
or IR OC/APAP. Overall, the formulations that produced higher
oxycodone C.sub.max and AUC also produced greater drug liking, drug
high, and good drug effects than those that produced lower
oxycodone concentrations (see FIGS. 83 to 88). Pharmacokinetic and
pharmacodynamic results for good drug effects (results not shown)
were similar to those for drug high. As shown in Table 96, strong
correlations were observed between oxycodone C.sub.max and
AUC.sub.0-x and E.sub.max and AUE.sub.0-x, respectively, for drug
liking, drug high, and good drug effects (R.sup.2=0.711-0.997).
Specifically, larger oxycodone C.sub.max values were correlated
with a higher E.sub.max for all PD assessments. Analyses also
showed strong correlations for AUE.sub.0-4h and AUE.sub.0-8h with
C.sub.max (R.sup.2=0.801-0.947). (See Table 96). The correlations
between AUE and oxycodone C.sub.max and T.sub.max were not as
strong as the comparisons of E.sub.max and C.sub.max (see Table 96;
see also FIGS. 89 to 92 presenting correlation plots for PK and PD
outcomes). The assessed PK parameters showed slightly stronger
relationship to the PD parameters for drug high compared with drug
liking and good drug effects (see FIGS. 89 to 92; data for good
drug effects not shown).
TABLE-US-00110 TABLE 96 Correlation Coefficients for Comparisons of
Pharmacodynamic and Pharmacokinetic Parameters AUE Correlation
Coefficient PD/PK Parameters Range Liking High Good Drug Effects
E.sub.max vs C.sub.max -- 0.9012 0.9364 0.8901 AUE vs C.sub.max 0-1
h 0.2945 0.4234 0.3497 0-2 h 0.5806 0.7098 0.6542 0-4 h 0.8349
0.9472 0.9101 0-8 h 0.8010 0.9339 0.8877 0-12 h 0.7609 0.8932
0.8310 AUC.sub.0-1 h 0-1 h 0.9656 0.9973 0.9831 AUC.sub.0-2 h 0-2 h
0.9126 0.9759 0.9550 AUC.sub.0-4 h 0-4 h 0.8703 0.9667 0.9420
AUC.sub.0-8 h 0-8 h 0.7976 0.9403 0.9105 AUC.sub.0-12 h 0-12 h
0.7105 0.8949 0.8432 AUE vs T.sub.max 0-1 h 0.6692 0.7359 0.6842
0-2 h 0.7731 0.7971 0.7926 0-4 h 0.5438 0.5447 0.5424 0-8 h 0.2785
0.3101 0.2811 0-12 h 0.2473 0.2385 0.2131
[0882] The results of these analyses demonstrate that intact high-
and low-dose CR OC/APAP have PK profiles that produce lower
C.sub.max and longer T.sub.max for OC than IR OC/APAP, which are
positively correlated with the PD outcomes of lower drug liking,
drug high, and good drug effects. Crushing CR OC/APAP further
slowed the rate of oxycodone release and produced corresponding
decreases in drug liking, drug high, and good drug effects relative
to those produced by comparable doses of intact CR OC/APAP and
intact and crushed IR OC/APAP. Previous analyses have demonstrated
a strong correlation between oxycodone PK and self-reported drug
effects. In addition, abuse potential studies of other prescription
opioids that also conducted PK assessments have shown that lower
and more prolonged increases in opioid concentrations are
associated with lower drug liking, drug high, and good drug
effects, although specific correlation analyses were not conducted.
In total, the results of these analyses demonstrate that the
participant-reported drug effects resulting from CR OC/APAP
administration were strongly correlated with the oxycodone PK
profile. In particular, CR OC/APAP, with its PK profile of
decreased oxycodone C.sub.max and relatively lower early oxycodone
exposure, produced lower degrees of drug liking, drug high, and
good drug effects than those of IR OC/APAP, which produced higher
oxycodone C.sub.max and greater early oxycodone exposure.
[0883] All references cited herein are hereby incorporated by
reference. The foregoing is offered primarily for purposes of
illustration. It will be readily apparent to those skilled in the
art that further drugs can be included, and that the shapes,
components, additives, proportions, methods of formulation, and
other parameters described herein can be modified further or
substituted in various ways without departing from the spirit and
scope of the invention.
* * * * *